1,3-dihydro-1-(phenylalkyl)-2H-imidazol-2-one compounds and their use for treating allergic, atopic or inflammatory diseases

ABSTRACT

The present invention describes 1,3-dihydro-1-(phenylalkyl)-2H-imidazol-2-one compounds and their use for treating warm-blooded animals suffering from disease states related to an abnormal enzymatic or catalytic activity of phosphodiesterase IV (PDE IV), and/or disease states related to a physiologically detrimental excess of cytokines, in particular allergic, atopic and inflammatory diseases.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a 371 of PCT Application Ser. No. PCT/EP96/01394,filed Mar. 28, 1996, which claims priority from European PatentApplication Serial Nos. 95.200.868.8, filed on Apr. 6, 1995 and95.202.898.3, filed on Oct. 26, 1995.

The present invention concerns the use of1,3-dihydro-1-(phenylalkyl)-2H-imidazol-2-one derivatives for themanufacture of a medicament for treating warm-blooded animals sufferingfrom disease states related to an abnormal enzymatic or catalyticactivity of phosphodiesterase IV (PDE IV), and/or disease states relatedto a physiologically detrimental excess of cytokines, in particularallergic, atopic and inflammatory diseases. The present invention alsorelates to new compounds having PDE IV and cytokine inhibiting activity,processes for their preparation and compositions comprising said newcompounds.

1-[2-(3,4-diethoxyphenyl)ethyl]-1,2-dihydro-2H-imidazol-2-one and anumber of (1,3-dihydro- and1,3,4,5-tetrahydro-)(1-[2-(3,4-dimethoxyphenyl)propyl]- and1-[2-(3,4-dimethoxyphenyl)ethyl])-2H-imidazol-2-one derivatives arespecifically disclosed in U.S. Pat. No. 3,184,460 as therapeutic agentsacting on the central nervous system, in particular, as tranquilizers.Synthetic Communications (1985) 15(10), 883-889, discloses a syntheticpathway for the preparation of1,3,4,5-tetrahydro-1-[2-(3,4-dimethoxy-phenyl)ethyl]-3-phenylmethyl-2H-imidazol-2-one.In the Chemical and Pharmaceutical Bulletin (1980), 28(6), 1810-1813,1,3,4,5-tetrahydro-1,3-bis[2-(3,4-dimethoxyphenyl)ethyl]-2H-imidazol-2-oneand1,3,4,5-tetrahydro-1-[2-(3,4-dimethoxyphenyl)ethyl]-2H-imidazol-2-oneare disclosed as intermediates in the synthesis of a diazasteroidsystem. WO 94/12461, WO 94/14742 and WO 94/20446 generically describe anumber of 1-(phenylalkyl)-2-hydroxy-imidazole derivatives as selectivePDE IV inhibitors.

Unexpectedly, particular 1,3-dihydro-1-(phenylalkyl)-2H-imidazol-2-onederivatives show improved PDE IV inhibiting activity over the artcompounds. In addition, the compounds of the present invention werefound to display cytokine inhibiting activity. In view of thesepharmacological properties, the present compounds have therapeuticalutility in the treatment of disease states related to an abnormalenzymatic or catalytic activity of PDE IV, or disease states related toa physiologically detrimental excess of cytokines, in particularallergic, atopic and inflammatory diseases.

The present invention concerns the use of compounds of formula (I) forthe manufacture of a medicament for treating warm-blooded animalssuffering from disease states related to an abnormal enzymatic orcatalytic activity of phosphodiesterase IV (PDE IV), and/or diseasestates related to a physiologically detrimental excess of cytokines, inparticular allergic, atopic and inflammatory diseases, said compoundshaving the formula ##STR1## the N-oxide forms, the pharmaceuticallyacceptable acid or base addition salts and the stereochemically isomericforms thereof, wherein:

R¹ and R² each independently are hydrogen; C₁₋₆ alkyl; difluoromethyl;trifluoromethyl; C₃₋₆ cycloalkyl; a saturated 5-, 6- or 7-memberedheterocycle containing one or two heteroatoms selected from oxygen,sulfur or nitrogen; indanyl; bicyclo[2.2.1]-2-heptenyl;bicyclo[2.2.1]heptanyl; C₁₋₆ alkylsulfonyl; arylsulfonyl; or C₁₋₁₀ alkylsubstituted with one or two substituents each independently selectedfrom aryl, pyridinyl, thienyl, furanyl, C₃₋₇ cycloalkyl and a saturated5-, 6- or 7-membered heterocycle containing one or two heteroatomsselected from oxygen, sulfur or nitrogen;

R³ is hydrogen, halo or C₁₋₆ alkyloxy;

R⁴ is hydrogen; halo; C₁₋₆ alkyl; trifluoromethyl; C₃₋₆ cycloalkyl;carboxyl; C₁₋₄ alkyloxycarbonyl; C₃₋₆ cycloalkylaminocarbonyl; aryl;Het¹ ; or C₁₋₆ alkyl substituted with cyano, amino, hydroxy, C₁₋₄alkylcarbonylamino, aryl or Het¹ ; or

R⁴ is a radical of formula:

    --O--R.sup.6                                               (a- 1); or

    --NH--R.sup.7                                              (a- 2);

wherein

R⁶ is hydrogen; C₁₋₆ alkyl; C₁₋₆ alkyl substituted with hydroxy,carboxyl, C₁₋₄ alkyloxycarbonyl, amino, mono- or di(C₁₋₄ alkyl)amino,Het¹ or aryl;

R⁷ is hydrogen; C₁₋₆ alkyl; C₁₋₄ alkylcarbonyl; C₁₋₆ alkyl substitutedwith hydroxy, carboxyl, C₁₋₄ alkyloxycarbonyl, amino, mono- or di(C₁₋₄alkyl)amino, Het¹ or aryl;

R⁵ is hydrogen, halo, hydroxy or C₁₋₆ alkyl; or

R⁴ and R⁵ taken together may form a bivalent radical of formula:

    --(CH.sub.2).sub.n --                                      (b-1);

    --CH.sub.2 --CH.sub.2 --O--CH.sub.2 --CH.sub.2 --          (b-2);

    --CH.sub.2 --CH.sub.2 --N(R.sup.8)--CH.sub.2 --CH.sub.2 -- (b-3); or

    --CH.sub.2 --CH═CH--CH.sub.2 --                        (b-4);

wherein

n is 2, 3, 4, or 5;

R⁸ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkylsulfonyl or p-toluenesulfonyl;

Y is a direct bond, haloC₁₋₄ alkanediyl or C₁₋₄ alkanediyl;

--A--B-- is a bivalent radical of formula:

    --CR.sup.9 ═CR.sup.10 --                               (c-1); or

    --CHR.sup.9 --CHR.sup.10 --                                (c-2);

wherein each R⁹ and R¹⁰ independently is hydrogen or C₁₋₄ alkyl; and

L is hydrogen; C₁₋₆ alkyl; C₁₋₆ alkylcarbonyl; C₁₋₆ alkyloxycarbonyl;C₁₋₆ alkyl substituted with one or two substituents selected from thegroup consisting of hydroxy, C₁₋₄ alkyloxy, C₁₋₄ alkyloxycarbonyl, mono-and di(C₁₋₄ alkyl)amino, aryl and Het² ; C₃₋₆ alkenyl; C₃₋₆ alkenylsubstituted with aryl; piperidinyl; piperidinyl substituted with C₁₋₄alkyl or arylC₁₋₄ alkyl; C₁₋₆ alkylsulfonyl or arylsulfonyl;

aryl is phenyl or phenyl substituted with one, two or three substituentsselected from halo, hydroxy, C₁₋₄ alkyl, C₁₋₄ alkyloxy, C₃₋₆ cycloalkyl,trifluoromethyl, amino, nitro, carboxyl, C₁₋₄ alkyloxycarbonyl and C₁₋₄alkylcarbonylamino;

Het¹ is pyridinyl; pyridinyl substituted with C₁₋₄ alkyl; furanyl;furanyl substituted with C₁₋₄ alkyl; thienyl; thienyl substituted withC₁₋₄ alkylcarbonylamino; hydroxypyridinyl, hydroxypyridinyl substitutedwith C₁₋₄ alkyl or C₁₋₄ alkoxy-C₁₋₄ alkyl; imidazolyl; imidazolylsubstituted with C₁₋₄ alkyl; thiazolyl; thiazolyl substituted with C₁₋₄alkyl; oxazolyl; oxazolyl substituted with C₁₋₄ alkyl; isoquinolinyl;isoquinolinyl substituted with C₁₋₄ alkyl; quinolinonyl, quinolinonylsubstituted with C₁₋₄ alkyl; morpholinyl; piperidinyl; piperidinylsubstituted with C₁₋₄ alkyl, C₁₋₄ alkyloxycarbonyl or arylC₁₋₄ alkyl;piperazinyl; piperazinyl substituted with C₁₋₄ alkyl, C₁₋₄alkyloxycarbonyl or arylC₁₋₄ alkyl; and

Het² is morpholinyl; piperidinyl; piperidinyl substituted with C₁₋₄alkyl or arylC₁₋₄ alkyl; piperazinyl; piperazinyl substituted with C₁₋₄alkyl or arylC₁₋₄ alkyl; pyridinyl; pyridinyl substituted with C₁₋₄alkyl; furanyl; furanyl substituted with C₁₋₄ alkyl; thienyl or thienylsubstituted with C₁₋₄ alkyl or C₁₋₄ alkylcarbonylamino.

The present invention also relates to a method of treating warm-bloodedanimals suffering from disease states related to an abnormal enzymaticor catalytic activity of PDE IV, and/or disease states related to aphysiologically detrimental excess of cytokines, in particular allergic,atopic and inflammatory diseases, more in particular asthmatic andatopic diseases, most particular atopic dermatitis. Said methodcomprises the administration of a therapeutically effective amount of acompound of formula (I) or a N-oxide form, a pharmaceutically acceptableacid or base addition salt or a stereochemically isomeric form thereofin admixture with a pharmaceutical carrier.

Some of the compounds of formula (I) may also exist in their tautomericforms. Such forms although not explicitly indicated in the above formulaare intended to be included within the scope of the present invention.

In R¹ and R², the saturated 5-, 6- or 7-membered heterocycles containingone or two heteroatoms selected from oxygen, sulfur or nitrogen maysuitably be selected from heterocycles such as, for example,tetrahydrofuranyl, dioxolanyl, pyrrolidinyl, morpholinyl, piperidinyl,piperazinyl and tetrahydropyranyl. Said heterocyclic radicals areattached to the C₁₋₁₀ alkyl radical by any carbon atom or, whereappropriate, by a nitrogen atom.

As used herein the term halo is generic to fluoro, chloro, bromo andiodo; the term C₁₋₄ alkyl is meant to include straight chained orbranched saturated hydrocarbons having from 1 to 4 carbon atoms such as,for example, methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, propyl,2-methylpropyl and butyl; the term C₄₋₆ alkyl is meant to includestraight chained or branched saturated hydrocarbons having from 4 to 6carbon atoms such as, for example, 2-methylpropyl, butyl, 2-methylbutyl,pentyl, hexyl and the like; the term C₃₋₆ alkyl is meant to include C₄₋₆alkyl and the lower homologues thereof having 3 carbon atoms such as,for example, propyl and 1-methylethyl; the term C₂₋₆ alkyl is meant toinclude C₃₋₆ alkyl and the lower homologues thereof having 2 carbonatoms such as, for example, ethyl; the term C₁₋₆ alkyl is meant toinclude C₂₋₆ alkyl and the lower homologue thereof having 1 carbon atomsuch as, for example, methyl; C₁₋₁₀ alkyl is meant to include C₁₋₆ alkyland the higher homologues thereof having from 7 to 10 carbon atoms suchas, for example, heptyl, octyl, nonyl, decyl, 1-methylhexyl,2-methylheptyl and the like; the term C₃₋₆ alkenyl defines straight andbranch chained hydrocarbon radicals containing one double bond andhaving from 3 to 6 carbon atoms such as, for example, 2-propenyl,3-butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl and thelike; and the carbon atom of said C₃₋₆ alkenyl being connected to anitrogen atom preferably is saturated; the term C₃₋₆ cycloalkyl isgeneric to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; the termC₃₋₇ cycloaklyl is meant to include C₃₋₆ cycloalkyl and cycloheptyl; theterm C₁₋₂ alkanediyl is meant to include methylene, 1,2-ethanediyl and1,1-ethanediyl; the term C₁₋₃ alkanediyl is meant to include C₁₋₂alkanediyl and the higher homologues thereof being straight chained andbranched saturated bivalent hydrocarbon radicals having 3 carbon atoms,such as, for example, 1,3-propanediyl, 1,2-propanediyl; the term C₁₋₄alkanediyl is meant to include C₁₋₃ alkanediyl and the higher homologuesthereof having 4 carbon atoms such as, for example, 1,4-butanediyl,2-methyl-1,3-propanediyl and the like.

As used in the foregoing definitions and hereinafter, haloC₁₋₄alkanediyl is defined as mono- or polyhalosubstituted C₁₋₄ alkanediyl,in particular C₁₋₄ alkanediyl substituted with one or more fluor atoms.

The pharmaceutically acceptable acid addition salts as mentionedhereinabove are meant to comprise the acid addition salt forms which canconveniently be obtained by treating the base form of the compounds offormula (I) with appropriate acids such as inorganic acids, for example,hydrohalic acid, e.g. hydrochloric or hydrobromic, sulfuric, nitric,phosphoric and the like acids; or organic acids, such as, for example,acetic, hydroxyacetic, propanoic, lactic, pyruvic, oxalic, malonic,succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic,ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic,p-aminosalicylic, pamoic and the like acids. Conversely, said acidaddition salt forms can be converted in the free base forms by treatmentwith an appropriate base.

The compounds of formula (I) containing an acidic proton may also beconverted into their non-toxic metal or amine addition salt forms bytreatment with appropriate organic and inorganic bases. Appropriate basesalt forms comprise, for example, the ammonium salts, the alkali andearth alkaline metal salts, e.g. the lithium, sodium, potassium,magnesium, calcium salts and the like, salts with organic bases, e.g.the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts withamino acids such as, for example, arginine, lysine and the like.

The term addition salt also comprises the hydrates and solvent additionforms which the compounds of formula (I) are able to form. Examples ofsuch forms are e.g. hydrates, alcoholates and the like.

The N-oxide forms of the compounds of formula (I) are meant to comprisethose compounds of formula (I) wherein one or several nitrogen atoms areoxidized to the so-called N-oxide.

The term "stereochemically isomeric forms" as used hereinbefore definesall the possible isomeric forms which the compounds of formula (I) maypossess. Unless otherwise mentioned or indicated, the chemicaldesignation of compounds denotes the mixture of all possiblestereochemically isomeric forms, said mixtures containing alldiastereomers and enantiomers of the basic molecular structure. More inparticular, stereogenic centers may have the R- or S-configuration.

Whenever used hereinafter, the term compounds of formula (I) is meant toinclude also the N-oxide forms, the pharmaceutically acceptable acid orbase addition salts and all stereoisomeric forms.

Some of the compounds of formula (I) and some of the intermediates inthe present invention may contain an asymmetric carbon atom. Purestereochemically isomeric forms of said compounds and said intermediatescan be obtained by the application of art-known procedures. For example,diastereoisomers can be separated by physical methods such as selectivecrystallization or chromatographic techniques, e.g. counter currentdistribution, liquid chromatography and the like methods. Enantiomerscan be obtained from racemic mixtures by first converting said racemicmixtures with suitable resolving agents such as, for example, chiralacids, to mixtures of diastereomeric salts or compounds; then physicallyseparating said mixtures of diastereomeric salts or compounds by, forexample, selective crystallization or chromatographic techniques, e.g.liquid chromatography and the like methods; and finally converting saidseparated diastereomeric salts or compounds into the correspondingenantiomers. Pure stereochemically isomeric forms may also be obtainedfrom the pure stereochemically isomeric forms of the appropriateintermediates and starting materials, provided that the interveningreactions occur stereospecifically. The pure and mixed stereochemicallyisomeric forms of the compounds of formula (I) are intended to beembraced within the scope of the present invention.

An alternative manner of separating the enantiomeric forms of thecompounds of formula (I) and intermediates involves liquidchromatography, in particular liquid chromatography using a chiralstationary phase.

The compounds of formula (I) are deemed novel, provided that thecompound is other than:

1,3-dihydro-1-[2-(3,4-dimethoxyphenyl)propyl]-2H-imidazol-2-one;

1,3-dihydro-1-[2-(3,4-dimethoxyphenyl)propyl]-5-methyl-2H-imidazol-2-one;

1-[2-(3,4-dimethoxyphenyl)ethyl]-1,3,4,5-tetrahydro-2H-imidazol-2-one;

1,3-dihydro-1-[2-(3,4-dimethoxyphenyl)ethyl]-2H-imidazol-2-one;

1-[2-(3,4-dimethoxyphenyl)propyl]-1,3,4,5-tetrahydro-2H-imidazol-2-one;

1-[2-(3,4-diethoxyphenyl)ethyl]-1,3-dihydro-2H-imidazol-2-one;

1,3-bis[2-(3,4-dimethoxyphenyl)ethyl]-1,3,4,5-tetrahydro-2H-imidazol-2-one;or

1-[2-(3,4-dimethoxyphenyl)ethyl]-3-phenylmethyl-1,3,4,5-tetrahydro-2H-imidazol-2-one.

Thus, the invention concerns novel compounds having the formula ##STR2##the N-oxide forms, the pharmaceutically acceptable acid or base additionsalts and the stereochemically isomeric forms thereof, wherein:

R¹ and R² each independently are hydrogen; C₁₋₆ alkyl; difluoromethyl;trifluoromethyl; C₃₋₆ cycloalkyl; a saturated 5-, 6- or 7-memberedheterocycle containing one or two heteroatoms selected from oxygen,sulfur or nitrogen; indanyl; bicyclo[2.2.1]-2-heptenyl;bicyclo[2.2.1]heptanyl; C₁₋₆ alkylsulfonyl; arylsulfonyl; or C₁₋₁₀ alkylsubstituted with one or two substituents each independently selectedfrom aryl, pyridinyl, thienyl, furanyl, C₃₋₇ cycloalkyl and a saturated5-, 6- 7-membered heterocycle containing one or two heteroatoms selectedfrom oxygen, sulfur or nitrogen;

R³ is hydrogen, halo or C₁₋₆ alkyloxy;

R⁴ is hydrogen; halo; C₁₋₆ alkyl; trifluoromethyl; C₃₋₆ cycloalkyl;carboxyl; C₁₋₄ alkyloxycarbonyl; C₃₋₆ cycloalkylaminocarbonyl; aryl;Het¹ ; or C₁₋₆ alkyl substituted with cyano, amino, hydroxy, C₁₋₄alkylcarbonylamino, aryl or Het¹ ; or

R⁴ is a radical of formula:

    --O--R.sup.6                                               (a- 1); or

    --NH--R.sup.7                                              (a- 2);

wherein

R⁶ is hydrogen; C₁₋₆ alkyl; C₁₋₆ alkyl substituted with hydroxy,carboxyl, C₁₋₄ alkyloxycarbonyl, amino, mono- or di(C₁₋₄ alkyl)amino,Het¹ or aryl;

R⁷ is hydrogen; C₁₋₆ alkyl; C₁₋₄ alkylcarbonyl; C₁₋₆ alkyl substitutedwith hydroxy, carboxyl, C₁₋₄ alkyloxycarbonyl, amino, mono- or di(C₁₋₄alkyl)amino, Het¹ or aryl;

R⁵ is hydrogen, halo, hydroxy or C₁₋₆ alkyl; or

R⁴ and R⁵ taken together may form a bivalent radical of formula:

    --(CH.sub.2).sub.n --                                      (b-1);

    --CH.sub.2 --CH.sub.2 --O--CH.sub.2 --CH.sub.2 --          (b-2);

    --CH.sub.2 --CH.sub.2 --N(R.sup.8)--CH.sub.2 --CH.sub.2 -- (b-3); or

    --CH.sub.2 --CH═CH--CH.sub.2 --                        (b-4);

wherein

n is 2, 3, 4 or 5;

R⁸ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkylsulfonyl or p-toluenesulfonyl;

Y is a direct bond, haloC₁₋₄ alkanediyl or C₁₋₄ alkanediyl;

--A--B-- is a bivalent radical or formula:

    --CR.sup.9 ═C.sup.10 --                                (c-1); or

    --CHR.sup.9 --CHR.sup.10 --                                (c-2);

wherein each R⁹ and R¹⁰ independently is hydrogen or C₁₋₄ alkyl; and

L is hydrogen; C₁₋₆ alkyl; C₁₋₆ alkylcarbonyl; C₁₋₆ alkyloxycarbonyl;C₁₋₆ alkyl substituted with one or two substituents selected from thegroup consisting of hydroxy, C₁₋₄ alkyloxy, C₁₋₄ alkyloxycarbonyl, mono-and di(C₁₋₄ alkyl)amino, aryl and Het² ; C₃₋₆ alkenyl; C₃₋₆ alkenylsubstituted with aryl; piperidinyl; piperidinyl substituted with C₁₋₄alkyl or arylC₁₋₄ alkyl; C₁₋₆ alkylsulfonyl or arylsulfonyl;

aryl is phenyl or phenyl substituted with one, two or three substituentsselected from halo, hydroxy, C₁₋₄ alkyl, C₁₋₄ alkyloxy, C₃₋₆ cycloalkyl,trifluoromethyl, amino, nitro, carboxyl, C₁₋₄ alkyloxycarbonyl and C₁₋₄alkylcarbonylamino;

Het¹ is pyridinyl; pyridinyl substituted with C₁₋₄ alkyl; furanyl;furanyl substituted with C₁₋₄ alkyl; thienyl; thienyl substituted withC₁₋₄ alkylcarbonylamino; hydroxypyridinyl, hydroxypyridinyl substitutedwith C₁₋₄ alkyl or C₁₋₄ alkoxyC₁₋₄ alkyl; imidazolyl; imidazolylsubstituted with C₁₋₄ alkyl; thiazolyl; thiazolyl substituted with C₁₋₄alkyl; oxazolyl; oxazolyl substituted with C₁₋₄ alkyl; isoquinolinyl;isoquinolinyl substituted with C₁₋₄ alkyl; quinolinonyl, quinolinonylsubstituted with C₁₋₄ alkyl; morpholinyl; piperidinyl; piperidinylsubstituted with C₁₋₄ alkyl, C₁₋₄ alkyloxycarbonyl or arylC₁₋₄ alkyl;piperazinyl; piperazinyl substituted with C₁₋₄ alkyl, C₁₋₄alkyloxycarbonyl or arylC₁₋₄ alkyl; and

Het² is morpholinyl; piperidinyl; piperidinyl substituted with C₁₋₄alkyl or arylC₁₋₄ alkyl; piperazinyl; piperazinyl substituted with C₁₋₄alkyl or arylC₁₋₄ alkyl; pyridinyl; pyridinyl substituted with C₁₋₄alkyl; furanyl; furanyl substituted with C₁₋₄ alkyl; thienyl or thienylsubstituted with C₁₋₄ alkyl or C₁₋₄ alkylcarbonylamino;

provided that the compound is not:

1,3-dihydro-1-[2-(3,4-dimethoxyphenyl)propyl]-2H-imidazol-2-one;

1,3-dihydro-1-[2-(3,4-dimethoxyphenyl)propyl]-5-methyl-2H-imidazol-2-one;

1-[2-(3,4-dimethoxyphenyl)ethyl]-1,3,4,5-tetrahydro-2H-imidazol-2-one;

1,3-dihydro-1-[2-(3,4-dimethoxyphenyl)ethyl]-2H-imidazol-2-one;

1-[2-(3,4-dimethoxyphenyl)propyl]-1,3,4,5-tetrahydro-2H-imidazol-2-one;

1-[2-(3,4-diethoxyphenyl)ethyl]-1,3-dihydro-2H-imidazol-2-one;

1,3bis[2-(3,4-dimethoxyphenyl)ethyl]-1,3,4,5-tetrahydro-2H-imidazol-2-one;or

1-[2-(3,4-dimethoxyphenyl)ethyl]-3-phenylmethyl-1,3,4,5-tetrahydro-2H-imidazol-2-one.

The subgroups as defined hereinafter are described as subgroups of thecompounds of formula (I) and are meant to be also subgroups of thecompounds of formula (I').

A first set of particular groups of compounds of formula (I) or ofcompounds of formula (I') consists of those wherein one or more of thefollowing provisions apply:

a) R¹ is hydrogen; C₁₋₆ alkyl; difluoromethyl; C₃₋₆ cycloalkyl;tetrahydrofuranyl; bicyclo[2.2.1]-2-heptenyl; arylsulfonyl; or C₁₋₁₀alkyl substituted with C₃₋₇ cycloalkyl or tetrahydrofuranyl; and R² isC₁₋₆ alkyl, difluoromethyl or trifluoromethyl;

b) R³ is hydrogen;

c) R⁴ is hydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, hydroxy, C₁₋₆ alkyloxy,trifluoromethyl, halo, amino, cyanoC₁₋₆ alkyl, C₁₋₆ alkylcarbonylamino,aryl, arylC₁₋₆ alkyl, Het¹ C₁₋₆ alkyl and R⁵ is hydrogen, C₁₋₆ alkyl orhydroxy, preferably R⁴ and R⁵ each independently are hydrogen or C₁₋₆alkyl;

d) R⁴ and R⁵ are taken together to form a radical of formula (b-1) or(b-2), preferably a radical of formula (b-1) wherein n is 2;

e) Y is a direct bond, methylene or 1,2-ethanediyl, preferably Y ismethylene;

f) L is hydrogen, C₁₋₆ alkyl, optionally substituted C₃₋₆ alkenyl, C₁₋₆alkyloxycarbonyl, C₁₋₆ alkyloxycarbonylC₁₋₆ alkyl or arylC₁₋₆ alkyl,preferably L is hydrogen;

g) --A--B-- is a bivalent radical of formula (c-1) or (c-2), preferablya bivalent radical of formula (c-1) wherein R⁹ and R¹⁰ are bothhydrogen.

An interesting subgroup within said first set of groups consists ofthose compounds of formula (I) or of compounds of formula (I') whereinR¹ is C₁₋₆ alkyl, C₃₋₆ cycloalkyl or C₁₋₁₀ alkyl substituted with C₃₋₇cycloalkyl and R² is C₁₋₆ alkyl.

Another interesting subgroup within said first set of groups consists ofthose compounds of formula (I) or of compounds of formula (I') wherein Yis methylene.

A second set of particular groups of compounds of formula (I) or ofcompounds of formula (I') consists of those wherein one or more of thefollowing provisions apply:

1) R¹ is hydrogen; a saturated 5-, 6- or 7-membered heterocyclecontaining one or two heteroatoms selected from oxygen, sulfur ornitrogen; bicyclo[2.2.1]-2-heptenyl; C₁₋₆ alkylsulfonyl; arylsulfonyl;or C₁₋₁₀ alkyl substituted with one or two substituents eachindependently selected from pyridinyl, thienyl, furanyl, C₃₋₇ cycloalkyland a saturated 5-, 6- or 7-membered heterocycle containing one or twoheteroatoms selected from oxygen, sulfur or nitrogen;

2) R² is hydrogen, C₃₋₆ cycloalkyl; a saturated 5-, 6- or 7-memberedheterocycle containing one or two heteroatoms selected from oxygen,sulfur or nitrogen; indanyl; bicyclo[2.2.1]-2-heptenyl;bicyclo[2.2.1]heptanyl; C₁₋₆ alkylsulfonyl; arylsulfonyl; or C₁₋₁₀ alkylsubstituted with one or two substituents each independently selectedfrom aryl, pyridinyl, thienyl, furanyl, C₃₋₇ cycloalkyl and a saturated5-, 6- or 7-membered heterocycle containing one or two heteroatomsselected from oxygen, sulfur or nitrogen;

3) R³ is halo or C₁₋₆ alkyloxy;

4) R⁴ is halo; trifluoromethyl; C₃₋₆ cycloalkyl; C₃₋₆cycloalkylaminocarbonyl; aryl; Het¹ ; or C₁₋₆ alkyl substituted withcyano, amino, hydroxy, C₁₋₄ alkylcarbonylamino, aryl or Het¹ ; or

R⁴ is a radical of formula:

    --O--R.sup.6                                               (a- 1); or

    --NH--R.sup.7                                              (a- 2);

wherein

R⁶ is C₁₋₆ alkyl substituted with hydroxy, carboxyl, C₁₋₄alkyloxycarbonyl, amino, mono- or di(C₁₋₄ alkyl)amino, Het¹ or aryl;

R⁷ is hydrogen; C₁₋₆ alkyl; C₁₋₄ alkylcarbonyl; C₁₋₆ alkyl substitutedwith hydroxy, carboxyl, C₁₋₄ alkyloxycarbonyl, amino, mono- or di(C₁₋₄alkyl)amino, Het¹ or aryl;

5) R⁵ is halo;

6) R⁵ is hydroxy and R⁴ is other than hydrogen or C₁₋₆ alkyl;

7) R⁴ and R⁵ taken together form a bivalent radical of formula:

    --(CH.sub.2).sub.n --                                      (b-1);

    --CH.sub.2 --CH.sub.2 --O--CH.sub.2 --CH.sub.2 --          (b-2);

    --CH.sub.2 --CH.sub.2 --N(R.sup.8)--CH.sub.2 --CH.sub.2 -- (b-3); or

    --CH.sub.2 --CH═CH--CH.sub.2 --                        (b-4);

wherein

n is 2, 3, 4 or 5;

R⁸ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkylsulfonyl or p-toluenesulfonyl;

8) --A--B-- is a bivalent radical of formula (c-2);

9) L is C₁₋₆ alkyl substituted with hydroxy or C₁₋₄ alkyloxy; C₃₋₆alkenyl; C₃₋₆ alkenyl substituted with aryl; C₁₋₆ alkylsulfonyl orarylsulfonyl.

An interesting subgroup within said second set of groups consists ofthose compounds of formula (I) or of compounds of formula (I') wherein

R⁴ is halo; trifluoromethyl; C₃₋₆ cycloalkyl; C₃₋₆cycloalkylaminocarbonyl; aryl; Het¹ ; or C₁₋₆ alkyl substituted withcyano, amino, hydroxy, C₁₋₄ alkylcarbonylamino, aryl or Het¹ ; or

R⁴ is a radical of formula:

    --O--R.sup.6                                               (a- 1); or

    --NH--R.sup.7                                              (a- 2);

wherein

R⁶ is C₁₋₆ alkyl substituted with hydroxy, carboxyl, C₁₋₄alkyloxycarbonyl, amino, mono- or di(C₁₋₄ alkyl)amino, Het¹ or aryl;

R⁷ is hydrogen; C₁₋₆ alkyl; C₁₋₄ alkylcarbonyl; C₁₋₆ alkyl substitutedwith hydroxy, carboxyl, C₁₋₄ alkyloxycarbonyl, amino, mono- or di(C₁₋₄alkyl)amino, Het¹ or aryl; or

R⁵ is halo; or

R⁴ and R⁵ taken together form a bivalent radical of formula:

    --(CH.sub.2).sub.n --                                      (b-1);

    --CH.sub.2 --CH.sub.2 --O--CH.sub.2 --CH.sub.2 --          (b-2);

    --CH.sub.2 --CH.sub.2 --N(R.sup.8)--CH.sub.2 --CH.sub.2 -- (b-3); or

    --CH.sub.2 --CH═CH--CH.sub.2 --                        (b-4);

wherein

n is 2, 3, 4 or 5;

R⁸ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkylsulfonyl or p-toluenesulfonyl.

Another interesting subgroup within said second set of groups consistsof those compounds of formula (I) or of compounds of formula (I')wherein R¹ is hydrogen; a saturated 5-, 6- or 7-membered heterocyclecontaining one or two heteroatoms selected from oxygen, sulfur ornitrogen; bicyclo[2.2.1]-2-heptenyl; C₁₋₆ -alkylsulfonyl; arylsulfonyl;or C₁₋₁₀ alkyl substituted with one or two substituents eachindependently selected from pyridinyl, thienyl, furanyl, C₃₋₇ cycloalkyland a saturated 5-, 6- or 7-membered heterocycle containing one or twoheteroatoms selected from oxygen, sulfur or nitrogen.

A third set of particular groups of compounds of formula (I) or ofcompounds of formula (I') consists of those wherein one or more of thefollowing provisions apply:

1) R¹ is hydrogen; C₁₋₆ alkyl; difluoromethyl; trifluoromethyl; asaturated 5-, 6- or 7-membered heterocycle containing one or twoheteroatoms selected from oxygen, sulfur or nitrogen; indanyl;bicyclo[2.2.1]-2-heptenyl; bicyclo[2.2.1]heptanyl; C₁₋₆ alkylsulfonyl;arylsulfonyl; or C₁₋₁₀ alkyl substituted with one or two substituentseach independently selected from aryl, pyridinyl, thienyl, furanyl, C₃₋₇cycloalkyl and a saturated 5-, 6- or 7-membered heterocycle containingone or two heteroatoms selected from oxygen, sulfur or nitrogen;

2) R² is hydrogen; C₃₋₆ cycloalkyl; a saturated 5-, 6- or 7-memberedheterocycle containing one or two heteroatoms selected from oxygen,sulfur or nitrogen; indanyl; bicyclo[2.2.1]-2-heptenyl;bicyclo[2.2.1]heptanyl; C₁₋₆ alkylsulfonyl; arylsulfonyl; or C₁₋₁₀ alkylsubstituted with one or two substituents each independently selectedfrom aryl, pyridinyl, thienyl, furanyl, C₃₋₇ cycloalkyl and a saturated5-, 6- or 7-membered heterocycle containing one or two heteroatomsselected from oxygen, sulfur or nitrogen;

3) R⁴ is halo; C₃₋₆ cycloalkyl; C₃₋₆ cycloalkylaminocarbonyl; aryl; Het¹; or C₁₋₆ alkyl substituted with amino, C₁₋₄ alkylcarbonylamino, aryl orHet¹ ; or

R⁴ is a radical of formula:

    --O--R.sup.6                                               (a- 1); or

    --NH--R.sup.7                                              (a- 2);

wherein

R⁶ is C₁₋₆ alkyl; C₁₋₆ alkyl substituted with hydroxy, carboxyl, C₁₋₄alkyloxycarbonyl, amino, mono- or di(C₁₋₄ alkyl)amino, Het¹ or aryl;

R⁷ is hydrogen; C₁₋₆ alkyl; C₁₋₄ alkylcarbonyl; C₁₋₆ alkyl substitutedwith hydroxy, carboxyl, C₁₋₄ alkyloxycarbonyl, amino, mono- or di(C₁₋₄alkyl)amino, Het¹ or aryl;

4) R⁵ is halo;

5) R⁴ and R⁵ taken together form a bivalent radical of formula:

    --(CH.sub.2).sub.n --                                      (b-1);

    --CH.sub.2 --CH.sub.2 --O--CH.sub.2 --CH.sub.2 --          (b-2);

    --CH.sub.2 --CH.sub.2 N(R.sup.8)--CH.sub.2 --CH.sub.2 --   (b-3); or

    --CH.sub.2 --CH═CH--CH.sub.2 --                        (b-4);

wherein

n is 2, 3, 4 or 5;

R⁸ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkylsulfonyl or p-toluenesulfonyl;

6) --A--B-- is a bivalent radical of formula (c-2).

An interesting subgroup within said third set of groups consists ofthose compounds of formula (I) or of compounds of formula (I') whereinR⁴ is halo; C₃₋₆ cycloalkyl; C₃₋₆ cycloalkylaminocarbonyl; aryl; Het¹ ;or C₁₋₆ alkyl substituted with amino, C₁₋₄ alkylcarbonylamino, aryl orHet¹ ; or

R⁴ is a radical of formula:

    --O--R.sup.6                                               (a 1); or

    --NH--R.sup.7                                              (a- 2);

wherein

R⁶ is C₁₋₆ alkyl; C₁₋₆ alkyl substituted with hydroxy, carboxyl, C₁₋₄alkyloxycarbonyl, amino, mono- or di(C₁₋₄ alkyl)amino, Het¹ or aryl;

R⁷ is hydrogen; C₁₋₆ alkyl; C₁₋₄ alkylcarbonyl; C₁₋₆ alkyl substitutedwith hydroxy, carboxyl, C₁₋₄ alkyloxycarbonyl, amino, mono- or di(C₁₋₄alkyl)amino, Het¹ or aryl; or

R⁵ is halo; or

R⁴ and R⁵ taken together form a bivalent radical of formula:

    --(CH.sub.2).sub.n --                                      (b-1);

    --CH.sub.2 --CH.sub.2 --O--CH.sub.2 --CH.sub.2 --          (b-2);

    --CH.sub.2 --CH.sub.2 --N(R.sup.8)--CH.sub.2 --CH.sub.2 -- (b-3); or

    --CH.sub.2 --CH═CH--CH.sub.2 --                        (b-4);

wherein

n is 2, 3, 4 or 5;

R⁸ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkylsulfonyl or p-toluenesulfonyl;

Another interesting subgroup within said third set of groups consists ofthose compounds of formula (I) or of compounds of formula (I') whereinR¹ is hydrogen; C₁₋₆ alkyl; difluoromethyl; trifluoromethyl; a saturated5-, 6- or 7-membered heterocycle containing one or two heteroatomsselected from oxygen, sulfur or nitrogen; indanyl;bicyclo[2.2.1]-2-heptenyl; bicyclo[2.2.1]heptanyl; C₁₋₆ alkylsulfonyl;arylsulfonyl; or C₁₋₁₀ alkyl substituted with one or two substituentseach independently selected from aryl, pyridinyl, thienyl, furanyl, C₃₋₇cycloalkyl and a saturated 5-, 6- or 7-membered heterocycle containingone or two heteroatoms selected from the oxygen, sulfur or nitrogen.

A fourth set of particular groups of compounds of formula (I) or ofcompounds of formula (I') consists of those wherein one or more of thefollowing provisions apply:

1) R¹ is hydrogen; a saturated 5-, 6- or 7-membered heterocyclecontaining one or two heteroatoms selected from oxygen, sulfur ornitrogen; indanyl; bicyclo[2.2.1]-2-heptenyl; bicyclo[2.2.1]heptanyl;C₁₋₆ alkylsulfonyl; arylsulfonyl; or C₁₋₁₀ alkyl substituted with one ortwo substituents each independently selected from aryl, pyridinyl,thienyl, furanyl, C₃₋₇ cycloalkyl and a saturated 5-, 6- or 7-memberedheterocycle containing one or two heteroatoms selected from oxygen,sulfur or nitrogen;

2) R² is hydrogen; C₃₋₆ cycloalkyl; a saturated 5-, 6- or 7-memberedheterocycle containing one or two heteroatoms selected from oxygen,sulfur or nitrogen; indanyl; bicyclo[2.2.1]-2-heptenyl;bicyclo[2.2.1]heptanyl; C₁₋₆ alkylsulfonyl; arylsulfonyl; or C₁₋₁₀ alkylsubstituted with one or two substituents each independently selectedfrom aryl, pyridinyl, thienyl, furanyl, C₃₋₇ cycloalkyl and a saturated5-, 6- or 7-membered heterocycle containing one or two heteroatomsselected from oxygen, sulfur or nitrogen.

3) R⁴ is C₁₋₆ alkyl; trifluoromethyl; C₃₋₆ cycloalkyl; carboxyl; C₁₋₄alkyloxycarbonyl; C₃₋₆ cycloalkylaminocarbonyl; or C₁₋₆ alkylsubstituted with cyano, amino, hydroxy, C₁₋₄ alkylcarbonylamino; or

R⁴ is a radical of formula:

    --O--R.sup.6                                               (a- 1); or

    --NH--R.sup.7                                              (a- 2);

wherein

R⁶ is C₁₋₆ alkyl substituted with carboxyl, C₁₋₄ alkyloxycarbonyl,amino, mono- or di(C₁₋₄ alkyl)amino, Het¹ or aryl;

R⁷ is hydrogen; C₁₋₆ alkyl; C₁₋₄ alkylcarbonyl; C₁₋₆ alkyl substitutedwith hydroxy, carboxyl, C₁₋₄ alkyloxycarbonyl, amino, mono- or di(C₁₋₄alkyl)amino, Het¹ or aryl;

4) R⁵ is C₁₋₆ alkyl;

5) R⁴ and R⁵ taken together form a bivalent radical of formula:

    --(CH.sub.2).sub.n --                                      (b-1);

    --CH.sub.2 --CH.sub.2 --O--CH.sub.2 --CH.sub.2 --          (b-2);

    --CH.sub.2 --CH.sub.2 --N(R.sup.8)--CH.sub.2 --CH.sub.2 -- (b-3); or

    --CH.sub.2 --CH═CH--CH.sub.2 --                        (b-4);

wherein

n is 2, 3, 4 or 5;

R⁸ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkylsulfonyl or p-toluenesulfonyl;

6) --A--B-- is a bivalent radical of formula (c-2).

An interesting subgroup within said fourth set of groups consists ofthose compounds of formula (I) or of compounds of formula (I') wherein

R⁴ is C₁₋₆ alkyl; trifluoromethyl; C₃₋₆ cycloalkyl; carboxyl; C₁₋₄alkyloxycarbonyl; C₃₋₆ cycloalkylaminocarbonyl; or C₁₋₆ alkylsubstituted with cyano, amino, hydroxy, C₁₋₄ alkylcarbonylamino; or

R⁴ is a radical of formula:

    --O--R.sup.6                                               (a- 1); or

    --NH--R.sup.7                                              (a- 2);

wherein

R⁶ is C₁₋₆ alkyl substituted with carboxyl, C₁₋₄ alkyloxycarbonyl,amino, mono- or di(C₁₋₄ alkyl)amino, Het¹ or aryl;

R⁷ is hydrogen; C₁₋₆ alkyl; C₁₋₄ alkylcarbonyl; C₁₋₆ alkyl substitutedwith hydroxy, carboxyl, C₁₋₄ alkyloxycarbonyl, amino, mono- or di(C₁₋₄alkyl)amino, Het¹ or aryl; or

R⁵ is C₁₋₆ alkyl; or

R⁴ and R⁵ taken together form a bivalent radical of formula:

    --(CH.sub.2).sub.n --                                      (b-1);

    --CH.sub.2 --CH.sub.2 --O--CH.sub.2 --CH.sub.2 --          (b-2);

    --CH.sub.2 --CH.sub.2 --N(R.sup.8)--CH.sub.2 --CH.sub.2 -- (b-3); or

    --CH.sub.2 --CH═CH--CH.sub.2 --                        (b-4);

wherein

n is 2, 3, 4 or 5;

R⁸ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkylsulfonyl or p-toluenesulfonyl.

Another interesting subgroup within said fourth set of groups consistsof those compounds of formula (I) or of compounds of formula (I')wherein R¹ hydrogen; a saturated 5-, 6- or 7-membered heterocyclecontaining one or two heteroatoms selected from oxygen, sulfur ornitrogen; indanyl; bicyclo[2.2.1]-2-heptenyl; bicyclo[2.2.1]heptanyl;C₁₋₆ alkylsulfonyl; arylsulfonyl; or C₁₋₁₀ alkyl substituted with one ortwo substituents each independently selected from aryl, pyridinyl,thienyl, furanyl, C₃₋₇ cycloalkyl and a saturated 5-, 6- or 7-memberedheterocycle containing one or two heteroatoms selected from oxygen,sulfur or nitrogen.

Preferred compounds are those compounds of formula (I) or of compoundsof formula (I') wherein R⁴ is C₃₋₆ cycloalkyl; C₃₋₆cycloalkylaminocarbonyl; or C₁₋₆ alkyl substituted with amino or C₁₋₄alkylcarbonylamino; or

R⁴ is a radical of formula:

    --O--R.sup.6                                               (a- 1); or

    --NH--R.sup.7                                              (a- 2);

wherein

R⁶ is C₁₋₆ alkyl substituted with carboxyl, C₁₋₄ alkyloxycarbonyl,amino, mono- or di(C₁₋₄ alkyl)amino, Het¹ or aryl;

R⁷ is hydrogen; C₁₋₆ alkyl; C₁₋₄ alkylcarbonyl; C₁₋₆ alkyl substitutedwith hydroxy, carboxyl, C₁₋₄ alkyloxycarbonyl, amino, mono- or di(C₁₋₄alkyl)amino, Het¹ or aryl; or

R⁴ and R⁵ taken together form a bivalent radical of formula:

    --(CH.sub.2).sub.n --                                      (b-1);

    --CH.sub.2 --CH.sub.2 --O--CH.sub.2 --CH.sub.2 --          (b-2);

    --CH.sub.2 --CH.sub.2 --N(R.sup.8)--CH.sub.2 --CH.sub.2 -- (b-3); or

    --CH.sub.2 --CH═CH--CH.sub.2 --                        (b-4);

wherein

n is 2, 3, 4 or 5;

R⁸ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkylsulfonyl or p-toluenesulfonyl.

Also preferred compounds are those compounds of formula (I) or ofcompounds of formula (I') wherein R¹ is hydrogen; a saturated 5-, 6- or7-membered heterocycle containing one or two heteroatoms selected fromoxygen, sulfur or nitrogen; bicyclo[2.2.1]-2-heptenyl; C₁₋₆alkylsulfonyl; arylsulfonyl; or C₁₋₁₀ alkyl substituted with one or twosubstituents each independently selected from pyridinyl, thienyl,furanyl, C₃₋₇ cycloalkyl and a saturated 5-, 6- or 7-memberedheterocycle containing one or two heteroatoms selected from oxygen,sulfur or nitrogen.

More preferred compounds are those compounds of formula (I) or ofcompounds of formula (I') wherein R¹ is C₃₋₆ cycloalkyl or methylsubstituted with C₃₋₇ cycloalkyl, R² is C₁₋₆ alkyl, R³ is hydrogen, R⁴is C₁₋₆ alkyl, R⁵ is hydrogen or C₁₋₆ alkyl, or R⁴ and R⁵ are takentogether to form a radical of formula (b-1) wherein n is 2, --A--B-- isa bivalent radical of formula (c-1) wherein R⁹ and R¹⁰ are bothhydrogen, Y is methylene and L is hydrogen.

Most preferred compounds are selected from:

1-[[1-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclopropyl]methyl]-1,3-dihydro-2H-imidazol-2-one;1-[2-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-methylpropyl]-1,3-dihydro-2H-imidazol-2-one;1-[2-[3-(cyclopentyloxy)-4-methoxyphenyl]propyl]-1,3-dihydro-2H-imidazole-2-one;and1-[2-[3-(cyclopropylmethoxy)-4-methoxyphenyl]propyl]-1,3-dihydro-2H-imidazol-2-one;the pharmaceutically acceptable acid or base addition salts and thestereochemically isomeric forms thereof.

Whenever used hereinafter, R¹ to R¹⁰, Y, --A--B-- and L are defined asunder formula (I) unless otherwise indicated.

The compounds of formula (I) can generally be prepared by N-alkylating a1,3-dihydro-2H-imidazol-2-one derivative of formula (II) with anappropriately substituted alkylating agent of formula (III), wherein W¹is a reactive leaving group such as, for example, a halogen. ##STR3##

Said N-alkylation may conveniently be performed in the presence of abase such as, for example, sodium hydride, butyllithium or sodiumbis(trimethylsilyl)amide, in a reaction-inert solvent such as, forexample, tetrahydrofuran, optionally cooled on an ice-bath. The reactionis preferably performed under a reaction inert atmosphere such as, forexample, oxygen free nitrogen. It may be advantageous to add to thereaction mixture a crown ether, e.g.1,4,7,10,13,16-hexaoxacyclooctadecane and the like or a complexing agentsuch as for example, tris[2-(2-methoxyethoxy)]ethanamine and the like.Stirring may enhance the rate of the reaction. In case intermediates offormula (II), wherein L is replaced by a suitable protecting group, areused in said N-alkylation reaction, compounds of formula (I) wherein Lis hydrogen, said compounds being represented by compounds of formula(I-a), may be obtained using art-known deprotection reactions.

In this and the following preparations, the reaction products may beisolated from the reaction medium and, if necessary, further purifiedaccording to methodologies generally known in the art such as, forexample, extraction, crystallization, trituration and chromatography.

Alternatively, compounds of formula (I) may be prepared by reacting anorganometallic intermediate of formula (IV), wherein M is an appropriatemetal ion or metalcomplex ion such as, for example, Li⁺, (MgBr)⁺, B(OH)₂⁺ or Sn(CH₃)₃ ⁺, with a suitable 1,3-dihydro-2H-imidazol-2-onederivative of formula (V) wherein W² is a reactive leaving group suchas, for example, a halogen. In case R⁴ and R⁵ are taken together andform a radical of formula (b-1), (b-2), (b-3) or (b-4), W² may also be acyanide moiety provided that the intermediate of formula (IV) is aGrignard reagent. ##STR4##

Said reaction may be performed in a reaction-inert solvent such as, forexample, dimethoxyethane, tetrahydrofuran or diethylether. Stirring andheating may enhance the rate of the reaction. In case intermediates offormula (V), wherein L is replaced by a suitable protecting group, areused in said reaction, compounds of formula (I) wherein L is hydrogen,said compounds being represented by compounds of formula (I-a), may beobtained using art-known deprotection reactions.

Compounds of formula (I-a) wherein --A--B-- is a radical of formula(c-1), said compounds being represented by formula (I-a-1), canconveniently be prepared by cyclization of an intermediate of formula(VI) or a functional derivative thereof in the presence of a suitableacid such as, for example, hydrochloric acid. ##STR5##

Said cyclization may be performed in a reaction inert solvent such as,for example, water, methanol or a mixture thereof. Stirring and heatingmay enhance the rate of the reaction.

In particular, compounds of formula (I-a-1) wherein R⁵ is hydroxy and Yis methylene, said compounds being represented by formula (I-a-1), maybe prepared by cyclization of an intermediate of formula (VI-1) whereinP is hydrogen or, preferably, is a trimethylsilyl protecting group or afunctional derivative thereof, in a manner analogous to the onedescribed for the preparation of a compound of formula (I-a-1) from anintermediate of formula (VI). ##STR6##

Compounds of formula (I-a-1) may also be prepared by cyclization of anintermediate of formula (VII) or a functional derivative thereof in thepresence of a suitable isocyanate, such as, for example, potassiumisocyanate or trimethylsilyl isocyanate. ##STR7##

Alternatively, compounds of formula (I-a-1) may also be prepared byreacting an intermediate of formula (VII) with a suitable cyanide suchas, for example, potassium cyanide, thus obtaining the correspondingN-cyanide derivative which may be further hydrolyzed in the presence ofan acid such as, for example, hydrochloric acid, keeping the pH of thereaction mixture basic. The thus formed corresponding ureum derivativeis then further cyclized in the presence of an excess of an acid suchas, for example, hydrochloric acid, to a compound of formula (I-a-1).##STR8##

Compounds of formula (I-a) wherein --A--B-- is a radical of formula(c-2), said compounds being represented by formula (I-a-2), can beobtained by cyclization of an intermediate of formula (VIII) or afunctional derivative thereof in the presence of a suitable reagent suchas, for example, phosgene, ureum or N,N'-carbonyldiimidazole. ##STR9##

The compounds of formula (I) can also be converted into each otherfollowing art-known procedures of functional group transformation.

For example, compounds of formula (I) wherein L is other than hydrogen,said compounds being represented by formula (I-b), may be prepared byreacting a compound of formula (I-a) with L"-W³ (IX), wherein L" is thesame as L defined under formula (I) but other than hydrogen and W³ is areactive leaving group such as, for example, a halogen atom. ##STR10##

Also art-known addition reactions may be used to convert compounds offormula (I-a) into compounds of formula (I-b).

Compounds of formula (I-b) wherein -A-B- is a radical of formula (c-2),said compounds being represented by formula (I-b-2), can be prepared byhydrogenation of compounds of formula (I-b) wherein -A-B- is a radicalof formula (c-1), said compounds being represented by formula (I-b-1),using art-known hydrogenation techniques. For instance, hydrogen in thepresence of a suitable catalyst such as, for example, palladium orplatinum supported on for instance charcoal may be used as anappropriate hydrogenation agent.

Compounds of formula (I-a-1) can be prepared by dehydrogenation ofcompounds of formula (I-a-2) using art-known dehydrogenation techniques.For instance, refluxing a compound of formula (I-a-2) in areaction-inert solvent such as, for example, p-xylene, in the presenceof a suitable catalyst such as, for example, palladium or platinumsupported on for instance charcoal may be used as a dehydrogenationtechnique.

The compounds of formula (I) may also be converted to the correspondingN-oxide forms following art-known procedures for converting a trivalentnitrogen into its N-oxide form. Said N-oxidation reaction may generallybe carried out by reacting the starting material of formula (I) with3-phenyl-2-(phenylsulfonyl)oxaziridine or with an appropriate organic orinorganic peroxide. Appropriate inorganic peroxides comprise, forexample, hydrogen peroxide, alkali metal or earth alkaline metalperoxides, e.g. sodium peroxide, potassium peroxide; appropriate organicperoxides may comprise peroxy acids such as, for example,benzenecarboperoxoic acid or halo substituted benzenecarboperoxoic acid,e.g. 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, e.g.peroxoacetic acid, alkylhydroperoxides, e.g. t-butyl hydroperoxide.Suitable solvents are, for example, water, lower alkanols, e.g. ethanoland the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone,halogenated hydrocarbons, e.g. dichloromethane, and mixtures of suchsolvents.

Intermediates mentioned hereinabove may be prepared following art-knowntechniques.

In particular, intermediates of formula (VI) may be prepared by firstN-acylating an amine of formula (X) with phenyl chloroformate or afunctional derivative thereof. Said N-acylation can conveniently beperformed in a reaction inert solvent such as, for example,dichloromethane, benzene or toluene, optionally cooled on an ice-bath,and in the presence of a base such as, for example,N,N-diethylethanamine or sodium-bicarbonate. The thus obtainedintermediate may be subsequently reacted with 2,2-(di-C₁₋₄alkyloxy)ethanamine or a functional derivative thereof, to form anintermediate of formula (VI). Said reaction can conveniently beperformed in a reaction inert solvent such as, for example, 1,4-dioxane,in the presence of a base such as, for example, N,N-diethylethanamine,and optionally in the presence of a base such as, for example,N,N-dimethyl-pyridinamine. Stirring and elevated temperatures mayenhance the rate of the reaction. ##STR11##

Also, intermediates of formula (VI) may be directly formed by reactingan intermediate of formula (X) with a suitable reagent such as, forexample, 2,2-(diC₁₋₄ alkyloxy)ethanisocyanate, phenyl[2,2-di(C₁₋₆alkyloxy)]ethyl)carbamate or a functional derivative of any one of saidreagents. ##STR12##

In particular, intermediates of formula (VI-1) may be prepared byreacting an intermediate of formula (X) wherein R⁵ is a hydroxy groupor, preferably, a protected hydroxy group, the protective group P beinga trimethylsilyl protecting group or a functional derivative thereof,and Y is methylene, said intermediates being represented by formula(X-1), with N-[2,2-di(C₁₋₄ alkyl)ethyl]-1H-imidazole-1-carboxamide or afunctional derivative thereof. ##STR13##

Intermediate of formula (VII) can be prepared by reacting an amine offormula (X) with an intermediate of formula (XI) wherein W⁴ is areactive leaving group such as, for example, a halogen. ##STR14##

Alternatively, intermediates of formula (VII) may be prepared byreacting an intermediate of formula (III) with 2,2-(diC₁₋₄alkyloxy)ethanamine or a functional derivative thereof. ##STR15##

Some of the intermediates of formula (X) are described in WO 92/00968,WO93/15044 an WO 93/15045.

In particular, intermediates of formula (X) may be prepared by reactingan intermediate of formula (III) with an intermediate of formula (XII)wherein M is an appropriate metal ion or metalcomplex ion such as, forexample, Li⁺ or (MgBr)⁺, and P is a suitable protecting group such as,for example, (1,1-dimethylethyl)oxycarbonyl. The thus obtained protectedintermediates of formula (X) may subsequently be deprotected byart-known techniques such as, for example, acid hydrolysis. ##STR16##

Intermediates of formula (X) wherein Y is a direct bond or C₁₋₃alkanediyl, said Y being represented by Y', and said intermediates beingrepresented by formula (X'), may be prepared by reducing the unsaturatedcarbon-nitrogen bond in the intermediates of formula (XIII) with asuitable reducing agent such as, for example, lithium aluminium hydrideor hydrogen in the presence of a catalyst such as, for example, Raneynickel. The cyanide moiety in the intermediates of formula (XIII) mayalso be replaced by a functional derivative thereof such as, forexample, an oxime moiety. ##STR17##

Some of the intermediates of formula (XIII) are described in WO92/00968, WO 93/15044 and WO 93/15045.

In particular, intermediates of formula (XIII) wherein R⁴ and R⁵ aretaken together to form a radical of formula (b-1) and Y' is a directbond, said intermediates being represented by formula (XIII-b), may beprepared by reacting an intermediate of formula (XIII) wherein --C(R⁴R⁵)--Y'-- is --CH₂ --, said intermediates being represented by formula(XIII-a), with W⁶ --(CH₂)_(n) --W⁶ (XV) wherein W⁶ is a reactive leavinggroup such as, for example, a halogen, and n is 2, 3, 4 or 5. ##STR18##

Said reaction may conveniently be performed in a reaction inert solventsuch as, for example, water, tetrahydrofuran or dimethylsulfoxide, andin the presence of benzyl-triethylammonium chloride and a base such as,for example, sodium hydroxide. Stirring and elevated temperatures mayenhance the rate of the reaction.

Intermediates of formula (X) wherein Y is methylene and R⁵ is hydrogen,said intermediates being represented by formula (X-a), may be preparedby reducing a nitro derivative of formula (XIV) with a suitable reducingagent such as, for example, lithium aluminium hydride. ##STR19##

Intermediates of formula (X-1) may be prepared by reacting anintermediate of formula (XVI), wherein R⁴ is restricted to thosemoieties that do not interface with the reaction such as, for example,hydrogen, optionally substituted C₁₋₆ alkyl, C₃₋₆ cycloalkyl, aryl andHet¹, with trimethylsilyl cyanide or a functional derivative thereof inthe presence of a suitable catalyst such as, for example, zinc iodine,and in a reaction-inert solvent such as, for example, dichloromethane;thus forming an intermediate of formula (XIII) wherein Y' is a directbond and R⁵ is hydroxy or, preferably, a protected hydroxy group, theprotective group P being a trimethysilyl protecting group or afunctional derivative thereof, said intermediates being represented byformula (XIII-c). Subsequently, the nitrile derivative of formula(XIII-c) may be reduced to the corresponding amine of formula (X-1)using art-known techniques such as, for example, reduction with hydrogenin the presence of a suitable catalyst such as, for example, Raneynickel. ##STR20##

The compounds of formula (I), the N-oxide forms, the pharmaceuticallyacceptable acid or base addition salts and the stereochemically isomericforms thereof, are potent inhibitors of the phosphodiesterase (PDE)isoenzymes of family IV (cAMP-specific family).

cAMP (adenosine cyclic 3',5'-monophosphate) is a key second messenger,the concentration of which affects particular cell activities throughactivation of enzymes such as kinases. PDE IV is known to hydrolyse cAMPto its corresponding inactive 5'-monophosphate metabolite. Hence,inhibition of PDE IV leads to an elevation of cAMP levels in particularcells such as the respiratory smooth muscle cell and in a wide varietyof inflammatory cells, i.e. certain lymphocytes, e.g. basophils,neutrophils and eosinophils, monocytes and mast-cells. A number ofallergic, atopic and inflammatory diseases are deemed to be caused byhigher-than-normal PDE IV concentrations which result in low cAMP levelsand hypersensitivity of the thus affected cells for excitatory stimuli.(Examples of said hypersensitivity are for example, excessive histaminerelease from basophils and mast cells or excessive superoxide anionradical formation by eosinophils.) Hence, the present compounds havingpotent phosphodiesterase IV inhibitory properties are deemed usefulagents in alleviating and/or curing allergic, atopic and inflammatorydiseases. The functional effects of PDE IV inhibitors are e.g.respiratory smooth muscle relaxation, bronchodilation, plateletaggregation inhibition and inhibition of white blood cell mediatorrelease. Examples of allergic diseases are bronchial asthma, cheilitis,conjunctivitis, contact dermatitis and eczema, irritable bowel disease,deshydroform eczema, urticaria, vasculitis, vulvitis; examples of atopicdiseases are dermatitis and eczema, winterfeet, asthma, allergicrhinitis; and related afflictions are, for example, psoriasis and otherhyperproliferative disease.

The present invention thus also relates to compound of formula (I) asdefined hereinabove for use as a medicine, in particular for use as ananti-asthmatic medicine or as a medicine for treating atopic diseases.Thus the compounds of the present invention may be used for themanufacture of a medicament for treating asthmatic or atopic diseases,more in particular atopic dermatitis.

The PDE IV inhibitory activity of the compounds of formula (I) may bedemonstrated in the test "Inhibition of recombinant human mononuclearlymphocyte (MNL) phosphodiesterase type IV B produced in insect cellswith a baculovirus vector". Several in vivo and in vitro tests may beused to demonstrate the usefulness of the compounds of formula (I) intreating the described allergic, atopic and inflammatory diseases. Suchtests are for instance, "Bronchoconstriction of the guinea pig tracheain vitro", "Bronchoconstriction of the guinea pig trachea in vivo " andthe in vivo test "Dextran-induced oedema formation in mouse ear".

Further, the present compounds have only very low inhibitory activity onthe phosphodiesterase isoenzymes of family III (cGMP-inhibited family).Inhibition of, in particular, PDE III leads to an elevation of cAMP inthe cardia muscle, thereby causing effects on the contractile force ofthe heart as well as on the relaxation of the heart. In the treatment ofthe described allergic, atopic and inflammatory diseases, cardiovasculareffects clearly are undesired. Hence, as the present compounds inhibitPDE IV at much lower concentrations as they inhibit PDE III, theirtherapeutic use may be adjusted to avoid cardiovascular side-effects.

Art-known PDE IV inhibitors often cause adverse gastro-intestinal sideeffects. Most of the present compounds, however, have few effects on thegastro-intestinal tract, which may be demonstrated in the test "Gastricemptying of a caloric meal in rats".

The designation PDE III and IV as used herein refers to theclassification by J. A. Beavo and D. H. Reifsnyder, TIPS Reviews, April1990, pp. 150-155.

The compounds of the present invention also have cytokine inhibitoryactivity. A cytokine is any secreted polypeptide that affects thefunction of other cells by modulating interactions between cells in theimmune or inflammatory response. Examples of cytokines are monokines andlymphokines and they may be produced by a wide variety of cells. Forinstance, a monokine is generally referred to as being produced andsecreted by a mononuclear cell, such as a macrophage and/or monocyte butmany other cells produce monokines, such as natural killer cells,fibroblasts, basophils, neutrophils, endothelial cells, brainastrocytes, bone marrow stromal cells, epideral keratinocytes, andβ-lymphocytes. Lymphokines are generally referred to as being producedby lymphocyte cells. Examples of cytokines include Interleukin-1 (IL-1),Interleukin-2 (IL-2), Interleukin-6 (IL-6), Interleukin-8 (IL-8),alpha-Tumor Necrosis Factor (αTNF) and beta-Tumor Necrosis Factor(βTNF).

The cytokine specifically desired to be inhibited is αTNF. Excessive orunregulated TNF production is implicated in mediating or exacerbating anumber of diseases including rheumatoid arthritis, rheumatoidspondylitis, osteoarthritis, gouty arthritis, and other arthriticconditions; sepsis, septic shock, endotoxic shock, gram negative sepsis,toxic shock syndrome, adult respiratory distress syndrome, cerebralmalaria, chronic pulmonary inflammatory disease, silicosis, pulmonarysarcoidosis, bone resorption diseases, reperfusion injury, graft versushost reaction, allograft rejections, fever and myalgias due toinfection, such as influenza, cachexia secondary to infection ofmalignancy, cachexia secondary to acquired immune deficiency syndrome(AIDS), AIDS, ARC (AIDS related complex), keloid formation, scar tissueformation, Crohn's disease, ulcerative colitis, or pyresis. The cytokineinhibitory activity of the compounds of formula (I), such as theinhibition of αTNF production, may be demonstrated in the in vitro test"Cytokine production in human whole blood cultures".

In addition, the compounds of the present invention are expected to showno or little endocrinological side-effects. This may be evidenced by,for instance, the "Testosterone in vivo" test, the "In vitro inhibitionof the aromatase activity"-test and the "In vivo inhibition of thearomatase activity"-test.

In view of their useful PDE IV and cytokine inhibiting properties, thesubject compounds may be formulated into various pharmaceutical formsfor administration purposes. To prepare the pharmaceutical compositionsof this invention, an effective amount of the particular compound, inbase or acid addition salt form, as the active ingredient is combined inintimate admixture with a pharmaceutically acceptable carrier, which maytake a wide variety of forms depending on the form of preparationdesired for administration. These pharmaceutical compositions aredesirably in unitary dosage form suitable, preferably, foradministration orally, rectally, topically, percutaneously, byinhalation or by parenteral injection. For example, in preparing thecompositions in oral dosage form, any of the usual pharmaceutical mediamay be employed, such as, for example, water, glycols, oils, alcoholsand the like in the case of oral iquid preparations such as suspensions,syrups, elixirs and solutions: or solid carriers such as starches,sugars, kaolin, lubricants, binders, disintegrating agents and the likein the case of powders, pills, capsules and tablets. Because of theirease in administration, tablets and capsules represent the mostadvantageous oral dosage unit form, in which case solid pharmaceuticalcarriers are obviously employed. For parenteral compositions, thecarrier will usually comprise sterile water, at least in large part,though other ingredients, for example, to aid solubility, may beincluded. Injectable solutions, for example, may be prepared in whichthe carrier comprises saline solution, glucose solution or a mixture ofsaline and glucose solution. Injectable suspensions may also be preparedin which case appropriate liquid carriers, suspending agents and thelike may be employed. In the compositions suitable for percutaneousadministration, the carrier optionally comprises a penetration enhancingagent and/or suitable wettable agent, optionally combined with suitableadditives of any nature in minor proportions, which additives do notcause any significant deleterious effects on the skin. Said additivesmay facilitate the administration to the skin and/or may be helpful forpreparing the desired compositions. These compositions may beadministered in various ways, e.g., as a transdermal patch, as a spot-onor as an ointment. As appropriate compositions for topical applicationthere may be cited all compositions usually employed for topicallyadministering drugs e.g. creams, gellies, dressings, shampoos,tinctures, pastes, ointments, salves, powders and the like. Applicationof said compositions may be by aerosol, e.g. with a propellent such asnitrogen, carbon dioxide, a freon, or without a propellent such as apump spray, drops, lotions, or a semisolid such as a thickenedcomposition which can be applied by a swab. In particular, semisolidcompositions such as salves, creams, gellies, ointments and the likewill conveniently be used.

In order to enhance the solubility and/or the stability of the compoundsof formula (I) in pharmaceutical compositions, it can be advantageous toemploy α-, β- or γ-cyclodextrins or their derivatives, in particularhydroxyalkyl substituted cyclodextrins, e.g.2-hydroxy-propyl-β-cyclodextrin. Also co-solvents such as alcohols mayimprove the solubility and/or the stability of the compounds of formula(I) in pharmaceutical compositions. In the preparation of aqueouscompositions, addition salts of the subject compounds are obviously moresuitable due to their increased water solubility.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form refers tophysically discrete units suitable as unitary dosages, each unitcontaining a predetermined quantity of active ingredient calculated toproduce the desired therapeutic effect in association with the requiredpharmaceutical carrier. Examples of such dosage unit forms are tablets(including scored or coated tablets), capsules, pills, powder packets,wafers, injectable solutions or suspensions and the like, and segregatedmultiples thereof.

In general it is contemplated that an effective daily amount would befrom 0.01 mg/kg to 10 mg/kg body weight, more preferably from 0.04 mg/kgto 5 mg/kg body weight. It is evident that said effective daily amountmay be lowered or increased depending on the response of the treatedsubject and/or depending on the evaluation of the physician prescribingthe compounds of the instant invention. The effective daily amountranges mentioned hereinabove are therefore guidelines only and are notintended to limited the scope or use of the invention to any extent.

The following examples are intended to illustrate and not to limit thescope of the present invention.

Experiment part

Compounds of formula (I) and some intermediates have a stereogeniccenter. In those cases where the racemate was separated into itsenantiomers, the stereochemically isomeric form which was first isolatedwas designated as "A" and the second as "B", without further referenceto the actual stereochemical configuation. Hereinafter, "DIPE" meansdiisopropylether, "DMF" means N,N-dimethylformamide and "THF" meanstetrahydrofuran.

A. Preparation of the intermediates EXAMPLE A.1

a) Under a N₂ flow, a solution of benzyltrimethylammonium dichloroiodate(78 g) in THF (250 ml) was added to a mixture of1-[3-(cyclopentyloxy)-4-methoxyphenyl]-ethanone (26.3 g) in THF (250 ml)while stirring. The resulting reaction mixture was stirred for 16 hoursat RT. The solvent was evaporated and the residue was redissolved indiethyl ether (300 ml). The mixture was added dropwise to a 5% Na₂ S₂ O₄solution (400 ml). The aqueous layer was extracted twice with diethylether (100 ml). The combined organic layers were washed twice with water(500 ml), dried (MgSO₄), filtered and the solvent evaporated. The crudeoil was crystallized from hexane. The precipitate was filtered off,washed with hexane and dried, yielding 11 g of2-chloro-1-[3-(cyclopentyloxy)-4-methoxyphenyl]ethanone. The filtratewas evaporated and the residue was crystallized from hexane. Theprecipitate was filtered off and dried, yielding 7.4 g (24.6%) of2-chloro-1-[3(cyclopentyloxy)-4-methoxyphenyl]ethanone (interm. 1).

b) Sodium bis(trimethylsilyl)amide (5 ml) was added to a solution of1,3-dihydro-2H-imidazol-2-one (0.84 g) in DMF (50 ml), stirred under aN₂ flow and cooled in an ice-bath. The reaction mixture was stirred for30 minutes. Intermediate 1 (2.69 g) was added portionwise and theresulting reaction mixture was stirred for 16 hours at RT, then for 2hours at 50° C. The reaction mixture was stirred in methyl isobutylketone/water (200 ml/50 ml). The solvent was evaporated and methylisobutyl ketone (100 ml) was added and azeotroped on the rotaryevaporator. The mixture was purified by column chromatography oversilica gel (eluent: CH₂ Cl₂ /(CH₃ OH/NH₃) 97/3). The desired fractionswere collected and the solvent was evaporated. The white solid wasstirred in diisopropyl ether, filtered off, washed with DIPE and dried,yielding 0.4 g (12.6%) of1-[2-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-oxo-ethyl]-1,3-dihydro-2H-imidazol-2-one(interm. 2; mp. 201.1° C.).

In a similar way were prepared:

1-[2-(3,4-dimethoxyphenyl)-2-oxoethyl]-1,3-dihydro-3-(phenylmethyl)-2H-imidazol-2-one(interm. 21; mp. 128.8° C.); ethyl3-[2-(3,4-dimethoxyphenyl)-2-oxoethyl]-2-oxo-1-imidazolidine-1-carboxylate(interm. 22).

EXAMPLE A.2

a) A mixture of benzyltriethylammonium chloride (1.7 g) and sodiumhydroxide (120 g) in water (50 ml) was stirred at 60-70° C.3-Cyclopentyloxy-4-methoxybenzene-acetonitrile (56 g) and1,2-dibromoethane (50 ml) were added dropwise and the mixture wasstirred overnight. 1,2-Dibromoethane (2×25 ml) was added and the mixturewas stirred overnight. THF (50 ml) and 1,2-dibromoethane (25 ml) wereadded and the mixture was stirred again overnight. 1,2-Dibromoethane (25ml) was added and the mixture was stirred for 3 days. The mixture wasdiluted with water and DIPE. The separated organic layer was dried(MgSO₄), filtered and the solvent evaporated, yielding 50.5 g ofproduct. A sample (24.5 g) was stirred up in petroleum ether and theprecipitate was filtered off, washed and dried, yielding 17 g (31%) of1-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclopropanecarbonitrile (interm.3; mp. 80.4° C.).

b) Under a N₂ flow, a mixture of intermediate 3 (3.7 g) in THF (50ml)was added dropwise to a suspension of lithium aluminium hydride (0.55g) in THF (50 ml), while stirring at 0° C. The resulting reactionmixture was stirred for one hour at RT, then for 2 hours at refluxtemperature. The reaction mixture was cooled to 0° C. on an ice-bath.First water (0.6 ml) and then a 15% aqueous NaOH solution (0.6 ml) wereadded, then water (1.8 ml) was added again. The reaction mixture wasfiltered over dicalite and the filtrate was evaporated, yielding 3.76 g(100%) 1-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclopropanemethanamine(interm. 4).

EXAMPLE A.3

A solution of 1-[3-(cyclopentyloxy)-4-methoxyphenyl]ethanone oxime (15.3g) in methanol/ammonia (350 ml) was hydrogenated for 3 hours with Raneynickel (3 g) as a catalyst. After uptake of H₂, the catalyst wasfiltered off, washed with methanol and the filtrate was evaporated.Toluene was added and azeotroped on the rotary evaporator, yielding14.45 g (100%) of(±)-3-(cyclopentyloxy)-4-methoxy-α-methylbenzene-methanamine (interm.5).

EXAMPLE A.4

a) Sodium hydride (2.8 g) was washed with n-hexane under a N₂ flow. THF(300 ml) was added and the mixture was cooled to -5° C. a 0°C.(2-propanone/CO₂ bath). Diethyl (cyanomethyl)phosphonate (11.5 ml) wasadded dropwise while stirring. The mixture was stirred for 5 mixtures. Asolution of 1-(3-cyclopentyloxy-4-methoxyphenyl)-ethanone (13.93 g) inTHF (30 ml) was added dropwise. Upon complete addition, the reactionmixture was allowed to warm to RT. The reaction mixture was poured outinto ice-water/NH₄ Cl and this mixture was extracted with DIPE. Theseparated organic layer was dried (MgSO₄), filtered and the solvent wasevaporated. The resultant oil was purified by column chromatography oversilica gel (eluent: CH₂ Cl₂ /n-hexane 70/30, upgrading to 90/10). thedesired fractions were collected and the solvent was evaporated. Toluenewas added and azeotroped on the rotary evaporator and the residue wascrystallized, yielding 15.7 g (100%) of(A)-3-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-butenenitrile (interm. 6).

b) A mixture of intermediate 6 (12.5 g) in methanol/ammonia (350 ml) washydrogenated at a temperature below 20° C. with Raney nickel (3 g) as acatalyst. After uptake of H₂, the catalyst was filtered off and thefiltrate was evaporated. Toluene was added and azeotroped on the rotaryevaporator, yielding 11.6 g (100%) of(±)-3-(cyclopentyloxy)-4-methoxy-γ-methylbenzenepropanamine (interm. 7).

EXAMPLE A.5

a) A mixture of 3-(cylcopentyloxy)-4-methoxybenzeneacetonitrile (20 g)in THF (200 ml) was stirred at -78° C. under a N₂ flow.N-(1-methylethyl)-2-propanamine lithium salt (45 ml) was added dropwiseand the resulting mixture was stirred for 30 minutes at -78° C.Iodomethane (13.5 g) was added dropwise and the resulting reactionmixture was allowed to warm to RT. The reaction mixture was stirred for2 hours. The mixture was quenched with a saturated aqueous NH₄ Clsolution (200 ml) and was extracted with CH₂ Cl₂ (3×φml). The separatedorganic layer was dried (MgSO₄), filtered and the solvent wasevaporated, yielding 17.7 g (100%) of(±)-3-(cyclopentyloxy)-4-methoxy-α-methylbenzeneacetonitrile (interm.8).

b) A mixture of intermediate 8 (17.7 g) in methanol/ammonia (100 ml) washydrogenated at 20° C. with Raney nickel (3 g) as a catalyst. Afteruptake of H₂, the catalyst was filtered off and the filtrate wasevaporated. Toluene was added and azeotroped on the rotary evaporator.The residue was purified by HPLC over Hypersil BDS (eluent: (0.5%ammonium acetate in H₂ O)/CH₃ OH/CH₃ CN 70/15/15, upgrading over10/80/10, to 0/0/100). The pure fractions were collected and the solventwas evaporated, yielding 9.7 g (54%) of(±)-3-(cyclopentyloxy)-4-methoxy-β-methylbenzeneethamamine (interm. 9).

EXAMPLE A.6

a) A mixture of intermediate 9 (9.7 g) and triethylamine (4.34 g) in CH₂Cl₂ (100 ml) was cooled on an ice-bath. Phenyl chloroformate (6.7 g) wasadded dropwise and the resulting reaction mixture was stirred for 48hours at RT. Water (200 ml) was added and the mixture was stirred for 10minutes. The organic layer was separated, dried (MgSO₄), filtered andthe solvent was evaporated. The residue was purified by columnchromatography over silica gel (eluent: CH₂ Cl₂). The pure fractionswere collected and the solvent was evaporated, yielding 11.2 g (78%) of(±)-phenyl [2-[3-(cyclopentyloxy)-4-methoxyphenyl]propyl]carbamate(interm. 10).

b) A mixture of 2,2-dimethoxyethanamine (3.504 g) andN,N-dimethyl-4-pyridinamine (1.85 g) in triethylamine (8.45 ml) wasadded to a solution of intermediate 10 (11.2 g) in 1,4-dioxane (150 ml),while stirring at RT. The reaction mixture was stirred and refluxed for12 hours. The solvent was evaporated and the residue was taken up inNaOH solutuion (200 ml; 1 N). This mixture was extracted with CH₂ Cl₂(2×100 ml). The organic layer was separated, washed with 1 N NaOH (100ml), dried (MgSO₄), filtered and the solvent was evaporated. The residuewas purified by short column chromatography over silica gel (eluent:ethylacetate/ (CH₃ OH/NH₃) 97.5/2.5). The desired fractions warecollected and the solvent was evaporated, yielding 11.2 g (97%) of(±)-N-[2-[3-(cyclopentyloxy)-4-methoxphenyl]propyl]-N'-(2,2-dimethoxyethyl)urea(interm. 11).

In a similar way were prepared:

(±)-N-[2-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-methylpropyl]-N'-(2,2-dimethoxyethyl)urea(interm. 12);

N-[[1-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclopropyl]methyl]-N'-(2,2-di-methoxyethyl)urea(interm. 13);

(±)-N-[3-[3-(cyclopentyloxy)-4-methoxyphenyl]butyl]-N'-(2,2dimethoxyethyl)urea(interm. 14);

(±)-N-[1-[3-(cyclopentyloxy)-4-methoxyphenyl]-N'-(2,2-dimethoxyethyl)urea(interm. 15).

EXAMPLE A.7

a) A mixture of 4-(chloromethyl)-2-(cyclopropylmethoxy)-1-methoxybenzene(7.4 g) in DMF (68 ml) was stirred at 60° C. A mixture of potassiumcyanide (4.26 g) in water (3.4 ml), previously heated to 80° C., wasadded dropwise. The resulting reaction mixture was stirred for 30minutes at 60° C. The reaction mixture was cooled, treated with water(47 ml), and extracted with DIPE. The separated organic layer was dried(Na₂ SO₄), filtered, and the solvent was evaporated, yielding 6.2 g(85%) of 3-(cyclopropylmethoxy)-4-methoxybenzeneacetonitrile (interm.16).

b) A mixture of intermediate 16 (5.93 g) in THF (60 ml) was stirred at-78° C. N-lithium-1-methyl-N-(1-methylethyl)ethanamine (1.89 ml; 2 M inTHF) was added dropwise and the resulting reaction mixture was stirredfor 30 minutes at -78° C. Methyl iodide (1.89 ml) was added dropwise andthe resulting reaction mixture was stirred for 2 hours at RT. Themixture was quenched with a saturated aqueous NH₄ Cl solution and thismixture was extracted with ethylacetate. The separated organic layer wasdried (Na₂ SO₄), filtered, and the solvent was evaporated. The residuewas purified by open column chromatography over silica gel (eluent:hexane/ethylacetate 4/1), then by HPLC over silica gel (eluent:hexane/ethylacetate 60/10). The pure fractions were collected and thesolvent was evaporated, yielding 3.92 g (62%) of(±)-3-(cyclopropylemthoxy)-4-methoxy-α-methylbenzeneacetonitrile(interm. 17)

c) A mixture of intermediate 17 (3.44 g) in methanol/ammonia (100 ml)was hydrogenated at RT, with Raney nickel (2.5 g) as a catalyst. Afteruptake of hydrogen, the catalyst was filtered off, and the filtrate wasevaporated, yielding 3.6 g (quantitative yield) of(±)-3-(cyclopropylemthoxy)-4-methoxy-β-methylbenzeneethanamine (interm.18).

d) A mixture of intermediate 18 (3.5 g) and triethylamine (2.88 ml) inCH₂ Cl₂ (35 ml) was stirred and cooled on an ice-bath. Phenylchloroformate (2.11 ml) was added dropwise and the resulting reactionmixture was stirred for 3 hours. The reaction mixture was washed withwater, then extracted with CH₂ Cl₂. The separated organic layer wasdried (Na₂ SO₄), filtered, and the solvent was evaporated, yielding 5.56g (quantitative yield) of (±)-phenyl[2-[3-(cyclopropylemthoxy)-4-methoxyphenyl]-propyl]carbamate (interm.19).

e) A mixture of 2,2-dimethoxyethylamine (2 ml), triethylamine (4.63 ml)and N,N-di-methyl-4-pyridinamine (1.02 g) in 1,4-dioxane (21 ml) wasadded dropwise to a solution of intermediate 19 (5.9 g) in 1,4-dioxane(62 ml), and the resulting reaction mixture was stirred and refluxedovernight. The solvent was evaporated and the residue was stirred inNaOH (80 ml; 1 N). The mixture was extracted with CH₂ Cl₂ and theseparated organic layer was washed with NaOH (40 ml; 1 N), dried (Na₂SO₄), filtered and the solvent evaporated. The residue was purified bycolumn chromatography over silica gel (eluent: CH₂ Cl₂ /2-propanone90/10 and 80/20). The desired fractions were collected and the solventwas evaporated, yielding 5.01 g (82%) of(±)-N-[2-[3-(cyclopropylmethoxy)-4-methoxyphenyl]propyl-N'-(2,2-dimethoxyethyl)urea(interm. 20.)

EXAMPLE A.8

a) Phenyl lithium (15 ml) was added to a solution of intermediate 21(3.52 g) in THF (100 ml), stirred at -78° C. and under a N₂ flow. Theresulting reaction mixture was stirred for 2 hours at -78° C. Themixture was allowed to warm to RT, while stirring for 1 hour. Water (50ml) was carefully added and the mixture was stirred for 20 minutes, thentwice extracted with CH₂ Cl₂ (100 ml). The separated organic layer wasdried (MgSO₄), filtered, and the solvent was evaporated. The residue wascrystallized from ethanol. The precipitate was filtered off, washed withethanol and diethyl ether, then dried, yielding 1.27 g of1-[2-(3,4-dimethoxy-phenyl)-2-oxoethyl]-1,3dihydro-2H-imidazol-2-one(interm. 23).

b) A mixture of intermediate 22 (0.5 g) and potassium carbonate (0.5 g)in ethanol (50 ml) was stirred and refluxed for 30 minutes, then cooled,poured out into water and extracted three times with CH₂ Cl₂. Theorganic layer was separated, and the solvent evaporated. The residue waspurified by column chromatography over silica gel (eluent: CH₂ Cl₂ /CH₃OH95/5). The pure fractions were collected and the solvent wasevaporated. The residue was crystallized from CH₃ CN. The precipitatewas filtered off and dried, yielding 1.8 g (41.7%) of1-[2-(3,4-dimethoxyphenyl)-2-oxoethyl]-2-imidazolidinone (interm. 24;mp. 166.6 °C.).

EXAMPLE A.9

a) A mixture of sodium hydride (8.64 g) in THF (700 ml) was stirred atRT under a N₂ flow. Diethyl cyanomethylphosphonate (31.86 g) was addeddropwise while keeping the temperature below 15° C. The reaction mixturewas stirred for 15 minutes. Intermediate 24 (15.84 g) was addedportionwise and stirring was continued for 2 hours. The reaction mixturewas cooled on an ice-bath, decomposed with an aqueous NH₄ Cl solutionand this mixture was extracted three times with CH₂ Cl₂. The separatedorganic layer was dried (MgSO₄), filtered, and the solvent wasevaporated. The residue was purified by column chromatography oversilica gel (eluent: ethylacetate/C₂ H₅ OH 99/1). The desired fractionwas collected and the solvent was evaporated, the residue was stirred indiisopropyl ether. The precipitate was filtered off and dried, yielding10.16 g (59%) of(E)-3-(3,4-dimethoxyphenyl)-4-(2-oxo-1-imidazolidinyl)-2- butenenitrile(interm. 25).

EXAMPLE A.10

a) A suspension of 1,1'-carbonyldiimidazole (162.15 g) in CH₂ Cl₂ (500ml) was stirred on an ice-bath. 2,2-Dimethoxyethanamine (105.14 g) wasadded dropwise and the resulting reaction solution was stirred for 16hours. The reaction mixture was cooled on ice, stirred for 30 minutes,and was allowed to crystallize. The precipitate was filtered off,stirred for 15 minutes in ethylacetate (250 ml) at RT, then cooled on anice-bath for 30 minutes. The precipitate was filtered off, washed twicewith DIPE (50 ml), then dried, yielding 137.4 g (69%) ofN-(2,2-dimethoxyethyl)-1-H-imidazole-1-carboxamide (interm. 26).

b) A mixture of 5-formyl-2-methoxyphenyl 4-methylbenzenesulfonate (59.1g) and zinc iodide (3 g) in CH₂ Cl₂ (250 ml) was stirred at RT. Asolution of trimethylsilanecarbonitrile (25 g) in CH₂ Cl₂ (100 ml) wasadded dropwise and the resulting reaction mixture was stirred for 2hours at RT. Water (100 ml) was added and the mixture was stirred for 15minutes. The layers ware separated and the aqueous phase was extractedtwice with CH₂ Cl₂. The separated organic layer was washed twice withwater (100 ml), dried (MgSO₄), filtered and the solvent evaporated.Toluene was added and azeotroped on the rotary evaporator. The residuewas stirred in DIPE, filtered off, and dried, yielding 74 g (94.6%) of(±)-5-[cyano[(trimethylsilyl)oxy]methyl]-2-methoxyphenyl4-methylbenzenesulfonate (interm 27).

c) (±)-5-[2-amino-1-[(trimethylsilyl)oxy]ethyl]-2-methoxyphenyl4-methylbenzenesulfonate (interm. 28) was prepared from intermediate 27according to the procedure described in Example A.7.c.

d) A mixture of intermediate 28 and intermediate 26 (35.8 g) in THF (500ml) was stirred and refluxed for 4 hours, then stirred overnight at RT.The solvent was evaporated, yielding a quantitative yield of(±)-5-[2-[[[(2,2-dimethoxyethyl)-amino]-carbonyl]amino]-1-[(trimethylsilyl)oxy]ethyl]-2-methoxyphenyl4-methylbenzenesulfonate (interm. 29).

B. Preparation of the final compounds EXAMPLE B.1

Hydrochloric acid (88.3 ml; 0.5 N) was added dropwise to a solution ofintermediate 11 (11.2 g) in methanol/water (2/1)(150 ml) while stirringat RT. The reaction mixture was stirred for 16 hours, then cooled on anice-bath. NaOH (44.15 ml; 1 N) was added dropwise and the mixture wasstirred for 15 minutes at 0°C. CH₂ Cl₂ (150 ml) was added and themixture was allowed to warm to RT. The mixture was extracted with CH₂Cl₂ (100 ml). The separated organic layer was dried (MgSO₄), filteredand the solvent was evaporated. The residue was purified by columnchromatography over silica gel (eluent: ethylacetate/(CH₃OH/NH₃)97.5/2.5). The desired fractions were collected and the solventwas evaporated. The residue (6 g) was repurified by HPLC over silica gel(eluent: CH₂ Cl₂ /CH₃ OH94/6) The pure fractions were collected and thesolvent was evaporated. The residue was triturated in n-hexane. Theprecipitate was filtered off, washed with n-hexane and dried, yielding5.5 g (60%) of(±)-1-[2-[3-(cyclopentyloxy)-4-methoxyphenyl]propyl]-1,3-dihydro-2H-imidazol-2-one(comp. 1).

EXAMPLE B.2

Compound 1 was purified over cellulose triacetate (15-25 μm, 75 cm,diameter: 5 cm, flow: 20 ml/min; eluent: C₂ H₅ OH/H₂ O 95/5). Twodesired fraction groups were collected and their solvent was evaporated,giving residue (I) and residue (II). Residue (I) was repurified by shortcolumn chromatography over silica gel (eluent: ethylacetate/ (CH₃OH/NH₃)97.5/2.5). The pure fractions were collected and the solvent wasevaporated. The residue was dried, yielding(A)-1-[2-[3-(cyclopentyloxy)-4-methoxyphenyl]propyl]-1,3-dihydro-2H-imidazol-2-one(comp. 6). Residue (II) was repurified by short column chromatographyover silica gel (eluent: ethylacetate/(CH₃ OH/NH₃) 97.5/2.5). The purefractions were collected and the solvent was evaporated. The residue wasdried, yielding(B)-1-[2-[3-(cyclopentyloxy)-4-methoxyphenyl]propyl]-1,3-dihydro-2H-imidazol-2-one(comp. 7).

EXAMPLE B.3

A mixture of intermediate 2 (1 g) in THF (50 ml) was stirred under a N₂flow at -78° C. Phenyllithium (3.52 ml; 1.8 M solution incyclohexane/ether 70/30) was added dropwise and the mixture was stirredfor 30 minutes at -78° C. The mixture was allowed to warm to RT andstirring was continued for 1 hour. More phenyllithium (1.5 ml) was addeddropwise at RT and the mixture was stirred for another 2 hours. Thereaction mixture was stirred an refluxed for one hour, then cooled on anice-bath and quenched with a saturated NH₄ Cl solution. This mixture wasextracted with CH₂ Cl₂ (3×100 ml). The separated organic layer was driedover MgSO₄, filtered and the solvent was evaporated. The residue waspurified by short column chromatography over silica gel (eluent: CH₂ Cl₂/CH₃ OH/(CH₃ OH/NH₃)90/5/5). The pure fractions were collected and thesolvent was evaporated. The residue was triturated in DIPE. Theprecipitate was filtered off, washed with DIPE and dried, yielding 0.2 g(16%) of(±)-1-[2-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-hydroxy-2-phenylethyl]-1,3-dihydro-2H-imidazol-2-one(comp. 8).

EXAMPLE B.4

A solution of sodium bis (trimethylsilyl)amide in THF (4.14 ml; 2M) wasadded to a solution of compound 5 (2.5 g) in DMF (25 ml), cooled in anice-bath, while stirring. The mixture was stirred for another 5 minutes.Ethyl bromoacetate (0.92 ml) was added in one portion, and the resultingreaction mixture was stirred overnight at RT. More sodiumbis(trimethylsilyl)amide (2 ml) was added and the reaction mixture wasstirred for 3 hours at RT. The reaction mixture was poured out intowater/NH₄ Cl. This mixture was extracted with DIPE and the separatedorganic layer was dried over MgSO₄, filtered and the solvent evaporated,yielding 3.3 g of a syrup containing compound 9. This fraction waspurified by column chromatography over silica gel (eluent: CH₂ Cl₂ /(CH₃OH/NH₃) 100/0, upgrading to 98/2. The desired fractions were collectedand the solvent was evaporated. The residue was taken up in ethylacetateand again the solvent was evaporated, yielding 0.7 g of a syrupcontaining compound 9. This fraction was redissolved in diethyl ether,solvent was removed and the residue was dried, yielding 0.65 g (20.2%)of (±)-ethyl3-[1-[3-(cyclopentyloxy)-4-methoxyphenyl]ethyl]-2,3-dihydro-2-oxo-1H-imidazole-1-acetate(comp. 9).

EXAMPLE B.5

a) HCl (37.82 ml; 0.5 N) was added dropwise to a stirring solution ofintermediate 20 (4.62 g) in methanol (48 ml) and water (24.95 ml). Thereaction mixture was stirred overnight at RT. The mixture was alkalizedwith Na₂ CO₃ and extracted with ethyl-acetate. The separated organiclayer was dried (Na₂ SO₄), filtered, and the solvent was evaporated. Theresidue was purified by column chromatography over silica gel (eluent:CH₂ Cl₂ /2-propanone 40/10, and CH₂ Cl₂ /CH₃ OH 94/4), then by HPLC oversilica gel (eluent: CH₂ Cl₂ /CH₃ OH 97/3). The pure fractions werecollected and the solvent was evaporated. The residue was dissolved inCH₂ Cl₂ and the solvent was evaporated. The residue was stirred up inDIPE for 1 hour, the precipitate was filtered off and dried, yielding2.66 g (65%) of(±)-1-[2-[3-(cyclopropylmethoxy)-4-methoxyphenyl]propyl]-1,3-dihydro-2-H-imidazol-2-one(comp. 10).

b) The procedure described in example B.5.a was repeated yielding 3.66 gof compound 10 which wa subsequently optically purified by chiral columnchromatography over Chiralpak AS (eluent: hexane/ethanol 70/30. Two purefractions were collected and the solvent was evaporated, yieldingfraction (A) and fraction (B). Each fractions was triturated in DIPE.Each precipitate was filtered off, washed with DIPE, and dried, yielding0.9 g (14%) of (A)-1-[2-[3-(cyclopropylmethoxy)-4-methoxyphenyl]propyl]-1,3-dihydro-2H-imidazol-2-one(comp. 22) and 0.9 g (14%) of(B)-1-[2-[3-(cyclopropylmethoxy)-4-methoxyphenyl]propyl]-1,3-dihydro-2H-imidazol-2-one(comp. 23).

EXAMPLE B.6

A mixture of intermediate 21 (1.76 g) and ammoniun acetate (5 g) inmethanol (100 ml) was hydrogenated at 50° C. with palladium on activatedcarbon (1 g) as a catalyst in the presence of thiophene (4%; 1 ml).After uptake of hydrogen, the catalyst was filtered off and the filtratewas evaporated. The residue was taken up into CH₂ Cl₂. The organicsolution was washed with a saturated aqueous K₂ CO₃ solution (2×100 ml),dried (MgSO₄), filtered and the solvent was evaporated. The residue wasdissolved in 2-propanol and converted into the hydrochloric acid salt(1:1) with HCl (6 N)/2-propanol. The precipitate was filtered off,washed with 2-propanol and DIPE, then dried, yielding 0.5 g (26%) of(±)-1-[2-amino-2-(3,4-dimethoxyphenyl)ethyl]-3-(phenylmethyl)-2-imidazolidinone(comp. 11; mp. 221.7° C.).

EXAMPLE B.7

A solution of intermediate 2 (5 g) in THF (100 ml) was stirred at 10° C.under a N₂ flow. Methlmagnesium chloride (15.8 ml) was added dropwiseand the resulting reaction mixture was allowed to warm to RT. Stirringwas continued for 30 minutes. The mixture was cooled to 0° C. Water (50ml) was added dropwise and this mixture was extracted with CH₂ Cl₂(2×100 ml). The separated organic layer was dried (MgSO₄), filtered, andthe solvent was evaporated. The separated organic layer was dried(MgSO₄), filtered and the solvent was evaporated. The residue waspurified by short column chromatography over silica gel (eluent: CH₂ Cl₂/CH₃ OH/(CH₃ OH/NH₃) 95/2.5/2.5). The desired fractions were collectedand the solvent was evaporated. The residue was triturated inethylacetate. The precipitate was filtered off, washed withethylacetate, then dried, yielding 1.4 g (26.7%) of(±)-1-[2-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-hydroxypropyl]-1,3-dihydro-2H-imidazol-2-one(comp. 12; mp. 136.2° C.).

EXAMPLE B.8

Sodium brorohydride (1.89 g) was added to a suspension of intermediate24 (5.29 g) in methanol (100 ml). The reaction mixture wa stirred at RTfor 1 hour. The solvent was evaporated. The residue was taken up in CH₂Cl₂ (100 ml). Water (30 ml) was added carefully and the mixture wasstirred at RT for 20 minutes. The separated organic layer was dried(MgSO₄) filtered and the solvent was evaporated. The residue wascrystallized from CH₃ CN. The precipitate was filtered off, washed withCH₃ CN and DIPE, then dried, yielding 1.71 g (32%) of(±)-1-[2-(3,4-dimethoxyphenyl)-2-hydroxyethyl]-2-imidazolidinone (comp.13; mp. 166.4° C.).

EXAMPLE B.9

Acetyl chloride (2.43 g) was added dropwise to a solution of compound 11(10 g) and triethylamine (3.13 g) in CH₂ Cl₂ (200 ml), stirred at 0° C.The reaction mixture was stirred overnight at RT. The mixture was washedwith water (100 ml). The organic layer was separated. The aqueous phasewas extracted with CH₂ Cl₂ (2×100 ml). The combined organics were dried(MgSO₄), filtered and the solvent evaporated. The residue was purifiedby short column chromatography over silica gel (eluent: CH₂ Cl₂ /(CH₂OH/NH₃) 98/2). The desired fractions were collected and the solvent wasevaporated. The residue was crystallized from ethylacetate. Theprecipitate was filtered off, washed with ethylacetate and DIPE, thendried, yielding 4.4 g (40%) of(±)-N-[1-(3,4-dimethoxyphenyl)-2-[2-oxo-3-(phenylmethyl)-1-imidazolidinyl]ethyl]acetamide(comp. 14; mp. 156.4° C.).

EXAMPLE B.10

A solution of(±)-1-[2-(3,4-dimethoxyphenyl)-2-ethoxyethyl]-1,3-dihydro-3-(phenylmethyl)-2H-imidazol-2-one(4.86 g) in THF (100 ml) was stirred at RT. Phenyllithium (1.278 g) wasadded dropwise and the mixture was stirred overnight at RT. The mixturewas carefully poured out into ice/water (200 ml), then extracted threetimes with CH₂ Cl₂ (150 ml). The separated organic layer was dried(MgSO₄), filtered, and the solvent was evaporated The residue waspurified by short column chromatography over silica gel (eluent: CH₂ Cl₂/(CH₃ OH/NH₃) 95/5). The desired fractions were collected and thesolvent was evaporated. The residue was crystallized from ethylacetate.The precipitate was filtered off, wased with ethylacetate and DIPE, thendried, yielding 0.1 g (3%) of(±)-1-[2(3,4-dimethoxyphenyl)-2-ethoxyethyl]-1,3-dihydro-2H-imidazol-2-one(comp. 15; mp. 133.6° C.).

EXAMPLE B.11

A mixture of compound 14 (4.4 g) in methanol (150 ml) was hydrogenatedat 50° C. with palladium on activated carbon (2 g) as a catalyst. Afteruptake of hydrogen, the catalyst was filtered off and the filtrate wasevaporated. The residue was crystallized from CH₃ CN. The precipitatewas filtered off, washed with CH₃ CN and DIPE, then dried, yielding 1.71g (51%) of(±)-N-[1-(3,4-dimethoxyphenyl)[2-(2-oxo-1-imidazolidinyl)ethyl]acetamide(comp. 16; mp. 169.1° C.).

EXAMPLE B.12

A mixture of intermediate 25 (1.97 g) in methanol (50 ml) washydrogenated with palladium on activated carbon (1 g) as a catalyst inthe presence of thiophene (4%) (1 ml). After uptake of hydrogen, thecatalyst was filtered off and the filtrate was evaporated. The residuewas purified by HPLC over silica gel (eluent: CH₂ Cl₂ /CH₃ OH 90/10).The pure fractions were collected and the solvent was evaporated. Theresidue was stirred in DIPE, filtered off and dried. This fraction wasrecrystallized from ethylacetate. The precipitate was filtered off anddried, yielding 0.96 g (48.7%) of(±)-β-(3,4-dimethoxyphenyl)-2-oxo-1-imidazolidinebutanenitrile (comp.17).

EXAMPLE B.13

a) A mixture of intermediate 29 (0.18 mol) and hydrochloric acid (270ml) in methanol (1000 ml) was stirred for 2 days at RT. The reactionmixture was cooled on an ice-bath. NaOH (270 ml) was added and thismixture was extracted with CH₂ Cl₂. The separated organic layer wasdried (MgSO₄), filtered, and the solvent was evaporated. The crude oilwas crystallized from DlPE/ethylacetate. The precipitate was filteredoff, washed with DlPE, then dried, yielding 32.2 g (44%) of(±)-5-[2-(2,3-dihydro-2-oxo-1H-imidazol-1-yl)-1-hydroxyethyl]-2-methoxyphenyl4-methylbenzenesulfonate (comp. 18).

b) A mixture of compound 18 (5 g), potassium hydroxide (5.6 g) inmethanol (100 ml) was stirred and refluxed for 2 hours. The reactionmixture was treated with acetic acid (8 g). This mixture was dilutedwith CH₂ Cl₂ (50 ml), and purified by column chromatography over silicagel (eluent: CH₂ Cl₂ /(CH₃ OH/NH₃) 97/3, upgrading to 90/10). The purefractions were collected and the solvent was evaporated. The residue wascrystallized from CH₃ CH. The precipitate was filtered off and dried,yielding 1.2 g (38.7%) of(±)-1,3-dihydro-1-[2-hydroxy-2-(3-hydroxy-4-methoxyphenyl)ethyl]-2H-imidazol-2-one(comp. 19).

EXAMPLE B.14

A solution of diethylaminosulfur trifluoride (1.9 g) in CH₂ Cl₂ (100 ml)was stirred at -78° C. under N₂ flow. A solution of(±)-1-[2-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-hydroxyethyl]-1,3-dihydro-2H-imidazol-2-one(4 g), prepared according to the procedure described in example B.13.a,in CH₂ Cl₂ (25 ml) was added dropwise at -78° C., and the resultingreaction mixture was stirred for 4 hours at RT. The mixture wasdecomposed with water and was extracted with CH₂ Cl₂. The separatedorganic layer was dried (MgSO₄), filtered, and the solvent wasevaporated. The residue was purified by column chromatography oversilica gel (eluent: CH₂ Cl₂ /CH₃ OH 97/3). The pure fractions werecollected and the solvent was evaporated. The residue was crystallizedfrom DlPE. The precipitate was filtered off, washed with DlPE, thendried, yielding 0.25 g of(±)-1-[2-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl-2-fluoroethyl]-1,3-dihydro-2H-imidazol-2-one.(comp.20).

EXAMPLE B.15

A mixture of1-[[1-(3,4-dimethoxyphenyl)cyclopropyl]methyl]-1,3-dihydro-2H-imidazol-2-one(1.9 g) in DMF (20 ml) was stirred at RT. Sodium hydride (60%) (0.28 g)was added portionwise over 15 minutes. The mixture was stirred for 30minutes. A solution of bromomethylbenzene (1.45 g) in DMF (5 ml) wasadded dropwise over 15 minutes. The reaction mixture was stirred for 1hour. The solvent was evaporated. The residue was purified over silicagel on a glass filter (eluent: CH₂ Cl₂ /CH₃ OH 95/5). The pure fractionswere collected and the solvent was evaporated. The residue wascrystallized from diethyl ether (20 ml). The precipitate was filteredoff and dried, yielding 1.3 g (51%) of1-[[1-(3,4-dimethoxyphenyl)cyclopropyl]methyl]-1,3-dihydro-3-(phenylmethyl)-2H-imidazol-2-one(comp. 21; mp 110.5° C.).

The following compounds were prepared according to one of the aboveexamples (Ex. No.).

                                      TABLE 1                                     __________________________________________________________________________      #STR21##                                                                       -                                                                          Co. Ex.                           Phys.                                         No. no. R.sup.1 R.sup.2 R.sup.4 R.sup.5 data                                __________________________________________________________________________    10  B.5.a                                                                             cC.sub.3 H.sub.5 --CH.sub.2 --                                                            CH.sub.3 --                                                                        CH.sub.3 --                                                                         H                                                18 B.13.a 4-CH.sub.3 --C.sub.6 H.sub.4 --SO.sub.2 -- CH.sub.3 -- HO-- H       19 B.13.b H-- CH.sub.3 -- HO-- H                                              20 B.14 cC.sub.3 H.sub.5 --CH.sub.2 -- CHF.sub.2 -- F-- H                     22 B.5.b cC.sub.3 H.sub.5 --CH.sub.2 -- CH.sub.3 -- CH.sub.3 -- H (A)                                          23 B.5.b cC.sub.3 H.sub.5 --CH.sub.2                                         -- CH.sub.3 -- CH.sub.3 -- H (B)                                               24 B.13.b H-- CH.sub.3 -- CH.sub.3 --                                        H                                             25 B.13.b H-- CH.sub.3 -- CH.sub.3 --O-- H                                    26 B.13.a cC.sub.3 H.sub.5 --CH.sub.2 -- CHF.sub.2 -- HO-- H                  27 B.13.a cC.sub.3 H.sub.5 --CH.sub.2 -- CH.sub.3 -- HO-- H                   28 B.1 cC.sub.3 H.sub.5 --CH.sub.2 -- CHF.sub.2 -- CH.sub.3 -- H                                               29 B.1 3-tetrahydrofuranyl CH.sub.3 --                                       CH.sub.3 -- H                                 30 B.1 cC.sub.5 H.sub.9 -- CF.sub.3 -- CH.sub.3 -- H                          31 B.1 cC.sub.6 H.sub.11 --CH.sub.2 -- CH.sub.3 -- CH.sub.3 -- H                                               32 B.1 cC.sub.5 H.sub.9 --CH.sub.2 --                                        CH.sub.3 -- CH.sub.3 -- H                     33 B.1 2-tetrahydrofuranyl-CH.sub.2 -- CH.sub.3 -- CH3 H                      34 B.1 C.sub.6 H.sub.5 --CH.sub.2 -- CHF.sub.2 -- CH.sub.3 -- H                                                35 B.1 3-tetrahydrofuranyl CH.sub.3 --                                       H H                                           36 B.1 bicyclo[2.2.1]-heptanyl CH.sub.3 -- CH.sub.3 -- H 89.4°                                         C.                                            37 B.1 cC.sub.5 H.sub.9 -- CHF.sub.2 -- CH.sub.3 -- H 80.6° C.                                          38 B.1 CHF.sub.2 -- CHF.sub.2 --                                             CH.sub.3 -- H 90.1° C.                 39 B.1 4-CH.sub.3 --C.sub.6 H.sub.4 --SO.sub.2 -- CH.sub.3 -- CH.sub.3                                        -- H                                          40 B.14 4-CH.sub.3 --C.sub.6 H.sub.4 --SO.sub.2 -- CH.sub.3 -- F-- H                                           41 B.14 cC.sub.3 H.sub.5 --CH.sub.2 --                                       CH.sub.3 -- F-- H                           __________________________________________________________________________

                                      TABLE 2                                     __________________________________________________________________________      #STR22##                                                                       -                                                                          Co.                                                                              Ex.                                Phys.                                     no. no. R.sup.4 R.sup.5 A--B L data                                         __________________________________________________________________________    11 B.6                                                                              NH.sub.2  H  CH.sub.2 --CH.sub.2                                                                 C.sub.6 H.sub.5 --CH.sub.2 --                                                              221.7° C.                          13 B.8 --OH H CH.sub.2 --CH.sub.2 H 166.4° C.                          14 B.9 CH.sub.3 --C(═O)--NH-- H CH.sub.2 --CH.sub.2 C.sub.6 H.sub.5                                           --CH.sub.2 -- 156.4° C.                                                 15 B.10 C.sub.2 H.sub.5 --O-- H                                              CH═CH H 133.6° C.                                                   16 B.11 CH.sub.3 --C(═O)--NH--                                           H CH.sub.2 --CH.sub.2 H 169.1.degree                                          . C.                                      17 B.12 NC--CH.sub.2 -- H CH.sub.2 --CH.sub.2 H                               42 B.1 C.sub.6 H.sub.5 --CH.sub.2 -- H CH═CH H                            43 B.1 C.sub.6 H.sub.5 --C.sub.2 H.sub.4 -- H CH═CH H                     44 B.1 3-pyridinyl-CH.sub.2 -- H CH═CH H 130.5° C.                 45 B.1 CF.sub.3 -- H CH═CH H 166.5° C.                             46 B.1 C.sub.4 H.sub.9 -- H CH═CH H  93.9° C.                      47 B.1 cC.sub.6 H.sub.11 -- H CH═CH H 188.5° C.                    48 B.1 (CH.sub.3).sub.2 CH-- H CH═CH H 119.1° C.                   49 B.1 (CH.sub.3).sub.2 CH--CH.sub.2 -- H CH═CH H 129.2° C.                                             50 B.1 C.sub.2 H.sub.5 -- H                                                  CH═CH H 124.6° C.                                                   51 B.2 C.sub.6 H.sub.5 -- OH                                                 CH═CH H 171.2° C.                                                   52 B.2 C.sub.6 H.sub.5 -- OH                                                 CH.sub.2 --CH.sub.2 H 154.4°                                           C.                                        53 B.15 CH.sub.3 -- H CH═CH C.sub.6 H.sub.5 --CH.sub.2 --  59.2.degr                                          ee. C.                                    54 B.15 CH.sub.3 -- H CH═CH CH.sub.2 ═CH--CH.sub.2 --                 55 B.15 CH.sub.3 -- H CH═CH C.sub.4 H.sub.9 --                            56 B.15 CH.sub.3 -- H CH═CH C.sub.2 H.sub.5 --O--C(═O)--C.sub.3                                           H.sub.6 --                                57 B.15 CH.sub.3 -- H CH═CH C.sub.6 H.sub.5 --CH═CH--CH.sub.2                                             --                                        58 B.15 C.sub.2 H.sub.5 --O-- H CH═CH C.sub.6 H.sub.5 --CH.sub.2                                              90.8° C.                           59 B.8 --OH H CH.sub.2 --CH.sub.2 C.sub.2 H.sub.5 --O--C(═O)--                                                104.8° C.                          60 B.8 --OH H CH═CH C.sub.6 H.sub.5 --CH.sub.2 -- 114.4°         __________________________________________________________________________                                          C.                                  

                                      TABLE 3                                     __________________________________________________________________________      #STR23##                                                                       -                                                                          Co.                                                                              Ex.                            Phys.                                         no. no. Y R.sup.4 R.sup.5 L data                                            __________________________________________________________________________    1  B.1 CH.sub.2                                                                            CH.sub.3 --                                                                       H   H             87.7° C.                              2 B.1 CH.sub.2 CH.sub.3 -- CH.sub.3 -- H 144.7° C.                     4 B.1 C.sub.2 H.sub.4 CH.sub.3 -- H H  96.6° C.                        5 B.1 direct bond CH.sub.3 -- H H  98.2° C.                            6 B.2 CH.sub.2 CH.sub.3 -- H H (A); 104.0° C.                          7 B.2 CH.sub.2 CH.sub.3 -- H H (B); 108.1° C.                          8 B.3 CH.sub.2 C.sub.6 H.sub.5 -- HO-- H 119.9° C.                     9 B.4 direct bond CH.sub.3 -- H C.sub.2 H.sub.5 --O--C(═O)--CH.sub.2                                       --                                           12 B.7 CH.sub.2 HO-- CH.sub.3 -- H 136.2° C.                           61 B.14 CH.sub.2 CH.sub.3 -- F-- H                                            62 B.14 CH.sub.2 F-- H H                                                      63 B.13.a CH.sub.2 HO-- H H  98.8° C.                                  64 B.1 CH(CH.sub.3) CH.sub.3 -- H H                                           65 B.1 CH.sub.2 H-- H H 133.6° C.                                    __________________________________________________________________________

                                      TABLE 4                                     __________________________________________________________________________      #STR24##                                                                       -                                                                          Co.                                                                              Ex.                               Phys.                                      no. no. R.sup.1 R.sup.2 R.sup.4 --R.sup.5 L data                            __________________________________________________________________________     3 B.1                                                                              cC.sub.5 H.sub.9 --                                                                CH.sub.3                                                                         --CH.sub.2 --CH.sub.2 --                                                                H            114.2° C.                           21 B.15 CH.sub.3 CH.sub.3 --CH.sub.2 --CH.sub.2 -- C.sub.6 H.sub.5                                               --CH.sub.2 110.5° C.                66 B.15 CH.sub.3 CH.sub.3 --CH.sub.2 --CH.sub.2 -- CH2═CH--CH.sub.2                                          --  93.8° C.                        67 B.15 CH.sub.3 CH.sub.3 --CH.sub.2 --CH.sub.2 -- C.sub.4 H.sub.9 --                                             68 B.1 cC.sub.5 H.sub.9 -- CH.sub.3                                          --C.sub.2 H.sub.4 --O--C.sub.2                                                H.sub.4 -- H 172.5° C.                                                  69 B.1 cC.sub.5 H.sub.9 -- CH.sub.3                                          --C.sub.5 H.sub.10 -- H 192.4°                                          C.                                        70 B.1 cC.sub.5 H.sub.9 -- CHF.sub.2 --CH.sub.2 --CH.sub.2 -- H                                                   71 B.1 cC.sub.5 H.sub.9 -- CH.sub.3                                          --C.sub.4 H.sub.8 -- H 207.3°                                          C.                                         72 B.1 cC.sub.5 H.sub.9 -- CH.sub.3 --C.sub.3 H.sub.6 -- H 187.2°                                          C.                                        73 B.15 CH.sub.3 CH.sub.3 --CH.sub.2 --CH.sub.2 -- C.sub.2 H.sub.5                                               --O--C(═O)--C.sub.3 H.sub.6 --                                             74 B.1 CH.sub.3 CH.sub.3 --CH.sub.2                                          --CH.sub.2 -- H 147.3° C.                                               75 B.15 CH.sub.3 CH.sub.3 --CH.sub.2                                          --CH.sub.2 -- 4-NO.sub.2 --C.sub.6                                           H.sub.4 --CH.sub.2 --                    __________________________________________________________________________

C. Pharmacological example

The PDE IV inhibitory activity, both in vitro and in vivo, of thecompounds of formula (I), including the compounds

1,3-dihydro-1-[2-(3,4-dimethoxyphenyl)propyl]-2H-imidazol-2-one (comp.76);

1,3-dihydro-1-[2-(3,4-dimethoxyphenyl)propyl]-5-methyl-2H-imidazol-2one(comp. 77);

1-[2-(3,4-dimethoxyphenyl)ethyl]-1,3,4,5-tetrahydro-2H-imidazol-2-one(comp. 78);

1,3-dihydro-1-[2-(3,4-dimethoxyphenyl)ethyl]-2H-imidazol-2-one (comp.79);

1-[2-(3,4-dimethoxyphenyl)propyl]-1,3,4,5-tetrahydro-2-H-imidazol-2-one(comp. 80);

1,3-dihydro-1-[2-(2-bromo-4,5-dimethoxyphenyl)ethyl]-2H-imidazol-2-one(comp. 81);

1-[2-(3,4-diethoxyphenyl)ethyl]-1,3-dihydro-2H-imidazol-2-one (comp.82);

1,3-dihydro-1-[2-(3,4-dimethoxyphenyl)-2-methoxy-ethyl]-2H-imidazol-2-one(comp. 83);

1,3-dihydro-1-[(3,4-dimethoxyphenyl)methyl]-2H-imidazol-2-one (comp.84);

1,3-dihydro-1-[3-(3,4-dimethoxyphenyl)propyl]-2H-imidazol-2-one (comp.85); and

1,3-dihydro-1-[2-(3,4-dimethoxyphenyl)ethyl]-3-methyl-2H-imidazol-2-one(comp. 86); is demonstrated by means of the following two examples.

EXAMPLE C.1

Inhibition of recombinant human mononuclear lymphocyte (MNL)phosphodiesterase type IV B produced in insect cells with a baculovirusvector

The alleviating and/or curing effect of the instant compounds onallergic and atopic diseases was assessed by an in vitro assay system todetect an inhibiting effect on the recombinant human MNLphosphodiesterase type IV B.

Seventy-two hours after infection with recombinant baculovirus, theinsect cells were harvested and pelleted at 500 g for 5 minutes. Thecells were lysed in 10 ml lysis-buffer consisting of 20 mM Tris, 10 mMEGTA, 2 mM Na₂ EDTA, 1% Triton-X-100, 1 mM Na₃ VO₄, 10 mM NaF, 2μg/ml ofleupeptine, pepstatine and aprotinine, 0.3 μg/ml benzamidine and 100μg/ml TPCK pH 7.5. After 5 minutes on ice, solubilized cells werecentrifuged at 4000 rpm for 15 minutes at 4° C. The resultingsupernatant was filtered through a 0.45 μm filter (Millipore) andbrought to TBS buffer (50 mM Tris, 150 mM NaCl pH 7.4).

The supernatant containing phosphodiesterase (PDE) type IV B, wassubsequently loaded onto a 5 ml anti-FLAG-M₂ affinity gel column,previously activated with 5 ml 100 mM glycine pH 3.5 and equilibratedwith 20 ml 50 mM Tris, 150 mM NaCl pH 7.4. After washing the column withequilibration buffer, PDE IV was eluted in 1.5 ml fractions containing37.5 μl 1M tris pH 8. The fractions were dialyzed overnight against 20mM Tris, 2 mM Na₂ EDTA and 400 mM NaCl pH 7.5 and tested for PDE IVactivity. Identification was done on SDS PAGE and Western Blot(anti-FLAG-M₂). Active fractions were pooled, brought to 10% glyceroland stored at -70° C.

The incubation mixture (pH 8) (200 μl) contained 20 mM Tris, 10 mMmagnesium sulphate, 0.8 μM ³ H-cAMP (310 mCi/mmole) and thephosphodiesterase type IV, the amount depending on the enzymaticactivity. A protein concentration was chosen that showed a linearincrease of phosphodiesterase activity during an incubation period ofmaximum 10 minutes at 37° C. and where less than 10% of the initialsubstrate was hydrolyzed.

When the effect of different compounds on phosphodiesterase activity wastested, the medium without cAMP was incubated with the compound(s) orits carrier (DMSO--1% final concentration) for 5 min. The enzymaticreaction was started by addition of ³ H-cAMP and stopped 10 min laterafter transferring the microtiter-plate in a waterbath at 100° C. for 5min. After cooling to room temperature, alkaline phosphatase (0.25μg/ml) was added and the mixture was incubated at 37° C. for 20 min. 100μl of the mixture was subsequently applied to a GF-Bfilter-microtiter-plate (Millipore) filled with 300 μl DEAE-Sephadex-A25suspension. The plate was washed 3 times with 75 μl 20 mM Tris pH 7.5and the filtrates were collected for counting in the Packard Top Countscintillation counter.

The inhibiting effect of the present compounds on recombinant human MNLphosphodiesterase PDE IV B was measured at different concentrations ofthe instant compounds. The IC₅₀ values (expressed in M) were calculatedgraphically from the thus obtained inhibition values. Table 5 showsavailable IC₅₀ values of the present compounds on recombinant human MNLPDE IV B.

                  TABLE 5                                                         ______________________________________                                        Comp.  IC.sub.50                                                                              Comp.    IC.sub.50                                                                             Comp.  IC.sub.50                               No. (in M) No. (in M) No. (in M)                                            ______________________________________                                        1      4.8 × 10.sup.-9                                                                  32       1.4 × 10.sup.-7                                                                 70     4.9 × 10.sup.-8                   2 5.2 × 10.sup.-8 33 2.3 × 10.sup.-6 71 6.9 ×                                                     10.sup.-7                               3 7.5 × 10.sup.-9 34 1.9 × 10.sup.-7 72 5.4 ×                                                     10.sup.-8                               4 5.5 × 10.sup.-7 35 1.8 × 10.sup.-7 74 2.9 ×                                                     10.sup.-7                               5 1.5 × 10.sup.-7 36 3.9 × 10.sup.-8 76 1.5 ×                                                     10.sup.-7                               6 4.1 × 10.sup.-9 37 .sup. 7.0 × 10.sup.-10 77 7.3 ×                                              10.sup.-6                               7 4.3 × 10.sup.-8 38 2.0 × 10.sup.-8 78 9.0 ×                                                     10.sup.-6                               8 1.9 × 10.sup.-6 61 5.9 × 10.sup.-8 79 7.7 ×                                                     10.sup.-7                               10  <1 × 10.sup.-8 62 1.7 × 10.sup.-8 80 3.2 ×                                                    10.sup.-6                               12 2.9 × 10.sup.-7 63 4.0 × 10.sup.-8 82 4.6 ×                                                    10.sup.-7                               22 4.5 × 10.sup.-8 64 2.6 × 10.sup.-7 83 2.7 ×                                                    10.sup.-6                               29 2.4 × 10.sup.-7 65 6.8 × 10.sup.-9 86 1.8 ×                                                    10.sup.-6                             ______________________________________                                    

EXAMPLE C.2

Dextran-induced oedema formation in mouse ear

Systemic injection of dextran T500 in normal, non-sensitized miceelicits increased vascular permeability, leading to extravasation andoedema of the extremities. When dextran is injected together with a bluedye, blueing of the ears is the most prominent feature of oedematousresponse.

Male Swiss mice weighting 24-26 g were orally pretreated with the testcompound dissolved in PEG-200 at different concentrations or solvent.One hour later, the mice were given an intravenous injection with anisotonic saline solution containing 12 mg/ml dextran T500 and 2.6 mg/mlpontamine sky-blue dye, in a volume of 0.1 ml per 10 g body weight. Onehour and forty-five minutes later, the animals are sacrificed by etherand their ears removed. Extraction and quantification of theextravasated dye is done as described by Van Wauwe and Goossens (DrugDev. Res. 1986, 8, 213-218).

The extravasation of the dye is characterized by the blueing value whichis defined as the concentration of the extracted dye in both ears. Thebackground blueing value was determined once as the mean blueing valueobtained by injecting a group of mice with a saline solution containingonly dextran T500 and the blue dye. Table 6 lists the percentageinhibition of the extravasation of the dye when compared with thebackground extravasation of the dye when the test compound wasadministered at a dose of 5 mg/kg. The test compounds indicated by anasterisk (*) were tested at a dose of 2.5 mg/kg.

                  TABLE 6                                                         ______________________________________                                        Comp.  %        Comp.    %       Comp.  %                                       No. inhibition No. inhibition No. inhibition                                ______________________________________                                         1     83.1      29*     90.7    61     90.4                                     2 34.0 30 44.9 62 100                                                         3 34.7  31* 50.4 63 69.3                                                      4 10.9 32 76.2 64 41.3                                                        5 35.1 33 65.8 65 63.7                                                        6 85.1 34 31.1 67 9.8                                                         7 67.0 35 90.1 69 3.7                                                         8 12.4 36 97.7 70 43.6                                                        9 10.2 37 75.7 71 26.0                                                       10 91.9 38 76.6 72 6.0                                                        11 26.8  41* 99.6 76 69.0                                                     12 87.5 43 13.1 77 35.8                                                       13 36.3 44 12.0 78 31.3                                                       14 32.3 45 47.4 79 61.6                                                       16 10.8 46 14.8 80 53.4                                                        19* 49.4 47 23.0 81 34.1                                                      20* 94.4 48 35.4 82 28.2                                                     22 83.5 50 34.4 83 18.6                                                       23 72.1 51 14.8 84 46.5                                                        24* 26.8 53 37.6 85 31.6                                                      26* 67.6 54 42.5 86 39.0                                                      27* 90.7 57 30.0                                                             28 86.1 59 51.7                                                             ______________________________________                                    

D. COMPOSITION EXAMPLES

The following formulations exemplify typical pharmaceutical compositionssuitable for systemic or topical administration to animal and humansubjects in accordance with the present invention.

"Active ingredient" (A.I.) as used throughout these examples relates toa compound of formula (I) or a pharmaceutically acceptable addition saltthereof.

EXAMPLE D.1

film-coated tablets

Preparation of tablet core

A mixture of 100 g of the A.I., 570 g lactose and 200 g starch was mixedwell and thereafter humidified with a solution of 5 g sodium dodecylsulfate and 10 g polyvinylpyrrolidone in about 200 ml of water. The wetpowder mixture was sieved, dried and sieved again. Then there was added100 g microcrystalline cellulose and 15 g hydrogenated vegetable oil.The whole was mixed well and compressed into tablets, giving 10.000tablets, each comprising 10 mg of the active ingredient.

Coating

To a solution of 10 g methyl cellulose in 75 ml of denaturated ethanolthere was added a solution of 5 g of ethyl cellulose in 150 ml ofdichloromethane. Then there were added 75 ml of dichloromethane and 2.5ml 1,2,3-propanetriol. 10 g of polyethylene glycol was molten anddissolved in 75 ml of dichloromethane. The latter solution was added tothe former and then there were added 2.5 g of magnesium octadecanoate, 5g of polyvinylpyrrolidone and 30 ml of concentrated color suspension andthe whole was homogenated. The tablet cores were coated with the thusobtained mixture in a coating apparatus.

EXAMPLE D.2

2% cream

75 mg stearyl alcohol, 2 mg cetyl alcohol, 20 mg sorbitan monostearateand 10 mg isopropyl myristate are introduced into a doublewall jacketedvessel and heated until the mixture has completely molten. This mixtureis added to a separately prepared mixture of purified water, 200 mgpropylene glycol and 15 mg polysorbate 60 having a temperature of 70 to75° C. while using a homogenizer for liquids. The resulting emulsion isallowed to cool to below 25° C. while continuously mixing. A solution of20 mg A.I., 1 mg polysorbate 80 and purified water and a solution of 2mg sodium sulfite anhydrous in purified water are next added to theemulsion while continuously mixing. The cream, 1 g of the A.I. ishomogenized and filled into suitable tubes.

EXAMPLE D.3

2% topical gel

To a solution of 200 mg hydroxypropyl β-cyclodextrine in purified wateris added 20 mg of A.I. while stirring. Hydrochloric acid is added untilcomplete dissolution and then sodium hydroxide is added until pH 6.0.This solution is added to a dispersion of 10 mg carrageenan PJ in 50 mgpropylene glycol while mixing. While mixing slowly, the mixture isheated to 50° C. and allowed to cool to about 35° C. whereupon 50 mgethyl alcohol 95% (v/v) is added. The rest of the purified water q.s. ad1 g is added and the mixture is mixed to homogenous.

EXAMPLE D.4

2% topical cream

To a solution of 200 mg hydroxypropyl β-cyclodextrine in purified wateris added 20 mg of A.I. while stirring. Hydrochloric acid is added untilcomplete dissolution and next sodium hydroxide is added until pH 6.0.While stirring, 50 mg glycerol and 35 mg polysorbate 60 are added andthe mixture is heated to 70° C. The resulting mixture is added to amixture of 100 mg mineral oil, 20 mg stearyl alcohol, 20 mg cetylalcohol, 20 mg glycerol monostearate and 15 mg sorbate 60 having atemperature of 70° C. while mixing slowly. After cooling down to below25° C., the rest of the purified water q.s. ad 1 g is added and themixture is mixed to homogenous.

EXAMPLE D.5

2% liposome formulation

A mixture of 10 g phosphatidyl choline and 1 g cholesterol in 7.5 gethyl alcohol is stirred and heated at 40° C. until completedissolution. 2 g A.I. microfine is dissolved in purified water by mixingwhile heating at 40° C. The alcoholic solution is added slowly to theaqueous solution while homogenizing during 10 minutes. 1.5 gHydroxypropylmethylcellulose in purified water is added while mixinguntil swelling is complete. The resulting solution is adjusted to pH 5.0with sodium hydroxide 1 N and diluted with the rest of the purifiedwater ad 100 g.

We claim:
 1. A method of treating warm-blooded animals suffering fromdisease states related to an abnormal enzymatic or catalytic activity ofphosphodiesterase IV (PDE IV), or disease states related to aphysiologically detrimental excess of cytokines, which comprisesadministering to such animal an effective amount of a compound offormula (I) said compound having the formula ##STR25## a N-oxide form, apharmaceutically acceptable acid or base addition salt or astereochemically isomeric form thereof, wherein:R¹ and R² eachindependently are hydrogen; C₁₋₆ alkyl; difluoromethyl; trifluoromethyl;C₃₋₆ cycloalkyl; a saturated 5-, 6- or 7-membered heterocycle containingone or two heteroatoms selected form oxygen, sulfur or nitrogen;indanyl; bicyclo[2.2.1]-2-heptenyl; bicyclo[2.2.1]heptanyl; C₁₋₆alkylsulfonyl; arylsulfonyl; or C₁₋₁₀ alkyl substituted with one or twosubstituents each independently selected from aryl, pyridinyl, thienyl,furanyl, C₃₋₇ cycloalkyl and a saturated 5-, 6- or 7-memberedheterocycle containing one or two heteroatoms selected from oxygen,sulfur or nitrogen; R³ is hydrogen, halo or C₁₋₆ alkyloxy; R⁴ ishydrogen; halo; C₁₋₆ alkyl; trifluoromethyl; C₃₋₆ cycloalkyl; carboxyl;C₁₋₄ alkyloxycarbonyl; C₃₋₆ cycloalkylaminocarbonyl; aryl; Het¹ ; orC₁₋₆ alkyl substituted with cyano, amino, hydroxy, C₁₋₄alkylcarbonylamino, aryl or Het¹ ; or R⁴ is a radical of formula:

    --O--R.sup.6                                               (a- 1); or

    --NH--R.sup.7                                              (a- 2);

wherein R⁶ is hydrogen; C₁₋₆ alkyl; C₁₋₆ alkyl substituted with hydroxy,carboxyl, C₁₋₄ alkyloxycarbonyl, amino, mono- or di(C₁₋₄ alkyl)amino,Het¹ or aryl; R⁷ is hydrogen; C₁₋₆ alkyl; C₁₋₄ alkylcarbonyl; C₁₋₆ alkylsubstituted with hydroxy, carboxyl, C₁₋₄ alkyloxycarbonyl, amino, mono-or di(C₁₋₄ alkyl)amino, Het¹ or aryl; R⁵ is hydrogen, halo, hydroxy orC₁₋₆ alkyl; or R⁴ and R⁵ taken together form a bivalent radical offormula:

    --(CH.sub.2).sub.n --                                      (b-1);

    --CH.sub.2 --CH.sub.2 --O--CH.sub.2 --CH.sub.2 --          (b-2);

    --CH.sub.2 --CH.sub.2 --N(R.sup.8)--CH.sub.2 --CH.sub.2 -- (b-3); or

    --CH.sub.2 --CH═CH--CH.sub.2 --                        (b-4);

whereinn is 2, 3, 4 or 5; R⁸ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkylsulfonylor p-toluenesulfonyl; Y is a direct bond, haloC₁₋₄ alkanediyl or C₁₋₄alkanediyl; --A--B-- is a bivalent radical of formula:

    --CR.sup.9 ═CR.sup.10 --                               (c-1); or

    --CHR.sup.9 --CHR.sup.10 --                                (c-2);

wherein each R⁹ and R¹⁰ independently is hydrogen or C₁₋₄ alkyl; and Lis hydrogen; C₁₋₆ alkyl; C₁₋₆ alkylcarbonyl; C₁₋₆ alkyloxycarbonyl; C₁₋₆alkyl substituted with one or two substituents selected from the groupconsisting of hydroxy, C₁₋₄ alkyloxy, C₁₋₄ alkyloxycarbonyl, mono- anddi(C₁₋₄ alkyl)amino, aryl and Het² ; C₃₋₆ alkenyl; C₃₋₆ alkenylsubstituted with aryl; piperidinyl; piperidinyl substituted with C₁₋₄alkyl or arylC₁₋₄ alkyl; C₁₋₆ alkylsulfonyl or arylsulfonyl; aryl isphenyl or phenyl substituted with one, two or three substituentsselected from halo, hydroxy, C₁₋₄ alkyl, C₁₋₄ alkyloxy, C₃₋₆ cycloalkyl,trifluoromethyl, amino, nitro, carboxyl, C₁₋₄ alkyloxycarbonyl and C₁₋₄alkylcarbonylamino; Het¹ is pyridinyl; pyridinyl substituted with C₁₋₄alkyl; furanyl; furanyl substituted with C₁₋₄ alkyl; thienyl; thienylsubstituted with C₁₋₄ alkylcarbonylamino; hydroxypyridinyl,hydroxypyridinyl substituted with C₁₋₄ alkyl or C₁₋₄ alkoxyC₁₋₄ alkyl;imidazolyl; imidazolyl substituted with C₁₋₄ alkyl; thiazolyl; thiazolylsubstituted with C₁₋₄ alkyl; oxazolyl; oxazolyl substituted with C₁₋₄alkyl; isoquinolinyl; isoquinolinyl substituted with C₁₋₄ alkyl;quinolinonyl, quinolinonyl substituted with C₁₋₄ alkyl; morpholinyl;piperidinyl; piperidinyl substituted with C₁₋₄ alkyl, C₁₋₄alkyloxycarbonyl or arylC₁₋₄ alkyl; piperazinyl; piperazinyl substitutedwith C₁₋₄ alkyl, C₁₋₄ alkyloxycarbonyl or arylC₁₋₄ alkyl; and Het² ismorpholinyl; piperidinyl; piperidinyl substituted with C₁₋₄ alkyl oraryC₁₋₄ alkyl; piperazinyl; piperazinyl substituted with C₁₋₄ alkyl orarylC₁₋₄ alkyl; pyridinyl; pyridinyl substituted with C₁₋₄ alkyl;furanyl; furanyl substituted with C₁₋₄ alkyl; thienyl or thienylsubstituted with C₁₋₄ alkyl or C₁₋₄ alkylcarbonylamino.
 2. The method ofclaim 1 whereinR¹ and R² each independently are hydrogen, C₁₋₆ alkyl,difluoromethyl, trifluoromethyl, C₃₋₆ cycloalkyl,bicyclo[2.2.1]-2-heptenyl or C₁₋₁₀ alkyl substituted with one or twosubstituents each independently selected from C₃₋₇ cycloalkyl and asaturated 5-, 6- or 7-membered heterocycle containing one or twoheteroatoms selected from oxygen, sulfur or nitrogen; and L is hydrogen;C₁₋₆ alkyl; C₁₋₆ alkyl substituted with hydroxy, C₁₋₄ alkyloxy, C₁₋₄alkyloxycarbonyl, mono- or di(C₁₋₄ alkyl)amino, aryl or Het² ; C₃₋₆alkenyl; C₃₋₆ alkenyl substituted with aryl; piperidinyl; piperidinylsubstituted with C₁₋₄ alkyl or aryl-C₁₋₄ alkyl; C₁₋₆ alkylsulfonyl orarylsulfonyl; aryl is phenyl or phenyl substituted with one, two orthree substituents selected from halo, C₁₋₄ alkyl, C₁₋₄ alkyloxy, C₃₋₆cycloalkyl, trifluoromethyl, amino and C₁₋₄ alkylcarbonylamino.
 3. Themethod of claim 1, whereinR¹ and R² each independently are hydrogen,C₁₋₆ alkyl, difluoromethyl, trifluoromethyl, C₃₋₆ cycloalkyl orbicyclo[2.2.1]-2-heptenyl; R⁴ is hydrogen; C₁₋₆ alkyl; trifluoromethyl;C₃₋₆ cycloalkyl; carboxyl; C₁₋₄ alkylcarbonyl; C₃₋₆cycloalkylaminocarbonyl; aryl; Het¹ ; or C₁₋₆ alkyl substituted withcyano, amino, hydroxy, C₁₋₄ alkylcarbonylamino, aryl or Het¹ ; or R⁴ isa radical of formula:

    --O--R.sup.6                                               (a- 1); or

    --NH--R.sup.7                                              (a- 2);

whereinR⁶ is hydrogen; C₋₆ alkyl; C₁₋₆ alkyl substituted with hydroxy,carboxyl, C₁₋₄ alkyloxycarbonyl, amino, mono- or di(C₁₋₄ alkyl)-amino,Het¹ or aryl; R⁷ is hydrogen; C₁₋₆ alkyl; C₁₋₄ alkylcarbonyl; C₁₋₆ alkylsubstituted with hydroxy, carboxyl, C₁₋₄ alkyloxycarbonyl, amino, mono-or di(C₁₋₄ alkyl)amino, Het¹ or aryl; R⁵ is hydrogen, hydroxy or C₁₋₆alkyl; or R⁴ and R⁵ taken together form a bivalent radical of formula:

    --(CH.sub.2).sub.n --                                      (b-1);

    --CH.sub.2 --CH.sub.2 --O--CH.sub.2 --CH.sub.2 --          (b-2);

    --CH.sub.2 --CH.sub.2 --NLR.sup.8)--CH.sub.2 --CH.sub.2 -- (b-3); or

    --CH.sub.2 --CH═CH--CH.sub.2 --                        (b-4);

whereinn is 2, 3, 4 or 5; R⁸ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkylsulfonylor p-toluenesulfonyl; Y is a direct bond or C₁₋₄ alkanediyl; --A--B-- isa bivalent radical of formula:

    --CR.sup.9 ═CR.sup.10 --                               (c-1); or

    --CHR.sup.9 --CHR.sup.10 --                                (c-2);

wherein each R⁹ and R¹⁰ independently is hydrogen or C₁₋₄ alkyl; and Lis hydrogen; C₁₋₆ alkyl; C₁₋₆ alkyl substituted with hydroxy, C₁₋₄alkyloxy, C₁₋₄ alkyloxycarbonyl, mono- or di(C₁₋₄ alkyl)amino, aryl orHet² ; C₃₋₆ alkenyl; C₃₋₆ alkenyl substituted with aryl; piperidinyl;piperidinyl substituted with C₁₋₄ alkyl or arylC₁₋₄ alkyl; C₁₋₆alkylsulfonyl or arylsulfonyl; aryl is phenyl or phenyl substituted withone, two or three substituents selected from halo, C₁₋₄ alkyl, C₁₋₄alkyloxy, C₃₋₆ cycloalkyl, trifluoromethyl, amino and C₁₋₄alkylcarbonylamino.
 4. The method of claim 1 whereinR⁴ is halo;trifluoromethyl; C₃₋₆ cycloalkyl; C₃₋₆ cycloalkylaminocarbonyl; aryl;Het¹ ; or C₁₋₆ alkyl substituted with cyano, amino, hydroxy, C₁₋₄alkylcarbonylamino, aryl or Het¹ ; or R⁴ is a radical of formula:

    --O--R.sup.6                                               (a- 1); or

    --NH--R.sup.7                                              (a- 2);

whereinR⁶ is C₁₋₆ alkyl substituted with hydroxy, carboxyl, C₁₋₄alkyloxycarbonyl, amino, mono- or di(C₁₋₄ alkyl)amino, Het¹ or aryl; R⁷is hydrogen; C₁₋₆ alkyl; C₁₋₄ alkylcarbonyl; C₁₋₆ alkyl substituted withhydroxy, carboxyl, C₁₋₄ alkyloxycarbonyl, amino, mono- or di(C₁₋₄alkyl)amino, Het¹ or aryl; or R⁵ is halo; or R⁴ and R⁵ taken togetherform a bivalent radical of formula:

    --(CH.sub.2).sub.n --                                      (b-1);

    --CH.sub.2 --CH.sub.2 --O--CH.sub.2 --CH.sub.2 --          (b-2);

    --CH.sub.2 --CH.sub.2 --N(R.sup.8)--CH.sub.2 --CH.sub.2 -- (b-3); or

    --CH.sub.2 --CH═CH--CH.sub.2 --                        (b-4);

whereinn is 2, 3, 4 or 5; R⁸ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkylsulfonylor p-toluenesulfonyl.
 5. The method of claim 1 wherein R¹ is hydrogen; asaturated 5-, 6- or 7-membered heterocycle containing one or twoheteroatoms selected from oxygen, sulfur or nitrogen;bicyclo[2.2.1]-2-heptenyl; C₁₋₆ alkylsulfonyl; arylsulfonyl; or C₁₋₁₀alkyl substituted with one or two substituents each independentlyselected from pyridinyl, thienyl, furanyl, C₃₋₇ cycloalkyl and asaturated 5-, 6- or 7-membered heterocycle containing one or twoheteroatoms selected from oxygen, sulfur or nitrogen.
 6. The method ofclaim 1 whereinR⁴ is halo; C₃₋₆ cycloalkyl; C₃₋₆cycloalkylaminocarbonyl; aryl; Het¹ ; or C₁₋₆ alkyl substituted withamino, C₁₋₄ alkylcarbonylamino, aryl or Het¹ ; or R⁴ is a radicalformula:

    --O--R.sup.6                                               (a- 1); or

    --NH--R.sup.7                                              (a- 2);

whereinR⁶ is C₁₋₆ alkyl; C₁₋₆ alkyl substituted with hydroxy, carboxyl,C₁₋₄ alkyloxycaronyl, amino, mono- or di(C₁₋₄ alkyl)amino, Het¹ or aryl;R⁷ is hydrogen; C₁₋₆ alkyl; C₁₋₄ alkylcarbonyl; C₁₋₆ alkyl substitutedwith hydroxy, carboxyl, C₁₋₄ alkyloxycarbonyl, amino, mono- or di(C₁₋₄alkyl)amino, Het¹ or aryl; or R⁵ is halo; or R⁴ and R⁵ taken togetherform a bivalent radical of formula:

    --(CH.sub.2).sub.n --                                      (b-1);

    --CH.sub.2 --CH.sub.2 --O--CH.sub.2 --CH.sub.2 --          (b-2);

    --CH.sub.2 --CH.sub.2 --N(R.sup.8)--CH.sub.2 --CH.sub.2 -- (b-3); or

    --CH.sub.2 --CH═CH--CH.sub.2 --                        (b-4);

wherein n is 2, 3, 4 or 5; R⁸ is hydrogen, C₁₋₆ alkyl, C₁₋₆alkylsulfonyl or p-roluenesulfonyl.
 7. The method of claim 1 wherein R¹is hydrogen; C₁₋₆ alkyl; difluoromethyl; trifluoromethyl; a saturated5-, 6- or 7-membered heterocycle containing one or two heteroatomsselected from oxygen, sulfur or nitrogen; indanyl;bicyclo[2.2.1]-2-heptenyl; bicyclo[2.2.1]heptanyl; C₁₋₆ alkylsulfonyl;arylsulfonyl; or C₁₋₁₀ alkyl substituted with one or two substituentseach independently selected from aryl, pyridinyl, thienyl, furanyl, C₃₋₇cycloalkyl and a saturated 5-, 6- or 7-membered heterocycle containinone or two heteroatoms selected from oxygen, sulfur or nitrogen.
 8. Themethod claim 1 wherein R⁴ is C₁₋₆ alkyl; trifluoromethyl; C₃₋₆cycloalkyl; carboxyl; C₁₋₄ alkyloxycarbonyl; C₃₋₆cycloalkylaminocarbonyl; or C₁₋₆ alkyl substituted with cyano, amino,hydroxy, C₁₋₄ alkylcarbonylamino; or R⁴ is a radical of formula:

    --O--R.sup.6                                               (a- 1); or

    --NH--R.sup.7                                              (a- 2);

whereinR⁶ is C₁₋₆ alkyl substituted with carboxyl, C₁₋₄alkyloxycarbonyl, amino, mono- or di(C₁₋₄ alkyl)amino, Het¹ or aryl; R⁷is hydrogen; C₁₋₆ alkyl; C₁₋₄ alkylcarbonyl; C₁₋₆ alkyl substituted withhydroxy, carboxyl, C₁₋₄ alkyloxycarbonyl, amino, mono- or di(C₁₋₄alkyl)amino, Het¹ or aryl; or R⁵ is C₁₋₆ alkyl; or R⁴ and R⁵ takentogether form a bivalent radical of formula:

    --(CH.sub.2).sub.n --                                      (b-1);

    --CH.sub.2 --CH.sub.2 --O--CH.sub.2 --CH.sub.2 --          (b-2); or

    --CH.sub.2 --CH.sub.2 --NCR.sup.8)--CH.sub.2 l --CH.sub.2 --(b-3); or

    --CH.sub.2 --CH═CH--CH.sub.2 --                        (b-4);

wherein is 2, 3, 4 or 5; R⁸ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkylsulfonylor p-toluenesulfonyl.
 9. The method of claim 1 wherein R¹ is hydrogen; asaturated 5-, 6- or 7-membered heterocycle containing one or twoheteroatoms selected from oxygen, sulfur or nitrogen; indanyl;bicyclo[2.2.1]-2-heptenyl; bicyclo[2.2.1]heptanyl; C₁₋₆ alkylsulfonyl;arylsulfonyl; or C₁₋₁₀ alkyl substituted with one or two substituentseach independently selected from aryl, pyridinyl, thienyl, furanyl, C₃₋₇cycloalkyl and a saturated 5-, 6- or 7-membered heterocycle containingone or two heteroatoms selected from oxygen, sulfur or nitrogen.
 10. Themethod of claim 1 whereinR⁴ is C₃₋₆ cycloalkyl; C₃₋₆cycloalkylaminocarbonyl; or C₁₋₆ alkyl substituted with amino or C₁₋₄alkylcarbonylamino; or R⁴ is a radical of formula:

    --O--R.sup.6                                               (a- 1); or

    --NH--R.sup.7                                              (a- 2);

whereinR⁶ is C₁₋₆ alkyl substituted with carboxyl, C₁₋₄alkyloxycarbonyl, amino, mono- or di(C₁₋₄ alkyl)amino, Het¹ or aryl; R⁷is hydrogen; C₁₋₆ alkyl; C₁₋₄ alkylcarbonyl; C₁₋₆ alkyl substituted withhydroxy, carboxyl, C₁₋₄ alkyloxycarbonyl, amino, mono- or di(C₁₋₄alkyl)amino, Het¹ or aryl; or R⁴ and R⁵ taken together form a bivalentradical of formula:

    --(CH.sub.2).sub.n --                                      (b-1);

    --CH.sub.2 --CH.sub.2 --O--CH.sub.2 --CH.sub.2 --          (b-2);

    --CH.sub.2 --CH.sub.2 --N(R.sup.8)--CH.sub.2 --CH.sub.2 -- (b-3); or

    --CH.sub.2 --CH═CH--CH.sub.2 --                        (b-4);

wherein n is 2, 3, 4 or 5; R⁸ is hydrogen, C₁₋₆ alkyl, C₁₋₆alkylsulfonyl or p-toluenesulfonyl.
 11. The method of claim 1 wherein R¹is C₁₋₆ alkyl, C₃₋₆ alkyl, C₃₋₆ cycloalkyl or C₁₋₁₀ alkyl substitutedwith C₃₋₇ cycloalkyl and R² is C₁₋₆ alkyl.
 12. The method of any one ofclaims 1 to 11 wherein Y is methylene.
 13. The method of any one ofclaims 1 to 11 wherein L is hydrogen.
 14. The method of claim 1 whereinthe compound is selected from1-[[1-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclopropyl]methyl]-1,3-dihydro-2H-imidazol-2-one;1-[2-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-methylpropyl]-1,3-dihydro-2H-imidazol-2-one;1-[2-[3-(cyclopentyloxy)-4-methoxyphenyl]propyl]-1,3-dihydro-2H-imidazol-2-one;and1-[2-[3-(cyclopropylmethoxy)-4-methoxyphenyl]propyl]-1,3-dihydro-2H-imidazol-2-one,a stereoisomeric form or a pharmaceutically acceptable acid additionsalt thereof.
 15. A method of treating allergic, atopic or inflammatorydiseases in warm blooded animals which comprises administering to ananimal in need of such treatment an effective amount of a compoundaccording to any one of claims 1 to
 14. 16. A method of treating atopicdermatitis in warm blooded animals which comprises administering to ananimal in need of such treatment an effective amount of a compoundaccording to any one of claims 1 to 14.